Is CEP55 p.Pro426Arg (c.1277C>G) pathogenic?

CEP55 p.Pro426Arg (c.1277C>G) is classified Uncertain significance in CEP55 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-02-16). AlphaMissense: likely benign (0.1205); Ultra-rare (popmax 0.0658%, mid); Associated with multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome.

How common is CEP55 p.Pro426Arg (c.1277C>G) in the general population?

CEP55 p.Pro426Arg (c.1277C>G) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

What do computational predictors say about CEP55 p.Pro426Arg (c.1277C>G)?

AlphaMissense predicts likely benign (score 0.1205) — an in-silico prediction, not a clinical call.

CEP55 p.Pro426Arg

Q: What condition is associated with CEP55 p.Pro426Arg (c.1277C>G)?

CEP55 p.Pro426Arg (c.1277C>G) is associated with multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome (ClinVar).

c.1277C>G · rs200014799 · VCV1027682

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1205 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome

Computational evidence

Protein change
AlphaMissense	0.1205	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -7.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 28 kb · p 0.0058 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0658% Middle Eastern · 4/6,082 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0195% 315/1,613,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.105%	955
Middle Easterngrpmax	0.0658%	1,521
Finnishnot grpmax-eligible	0.0656%	1,524
Remaining individualsnot grpmax-eligible	0.0336%	2,976
South Asian	0.0209%	4,794
European (non-Finnish)	0.0159%	6,277
Admixed American	0.0133%	7,493
African / African-American	0.00267%	37,436

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CEP55
Protein: p.Pro426Arg
Coding: c.1277C>G
MANE Select: NM_018131
dbSNP: rs200014799
Type: single nucleotide variant
Location: chr10:93528035 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.85 · 4 PDB
Residue 426: a UniProt-annotated variant site (in march); a UniProt-annotated variant site (in march; loss of protein localization to midbody ring; loss of function; fails to rescue craniofacial development when expressed in a zebrafish heterologous system); the 'required for localization to the interphase centrosome and to the midbody during cytokinesis' region

Full CEP55 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CEP55 p.Arg64Ter Pathogenic/Likely pathogenic ★★ same condition
CEP55 p.Arg86Ter Pathogenic ★★ same condition
CEP55 p.Ser425Ter Pathogenic ★★ same condition
CEP55 p.Val127Ile Uncertain significance ★★ ⚠ same condition
CEP55 c.1191+89A>G Benign ★★ same condition
CEP55 p.His378Leu Benign/Likely benign ★★ same condition
CEP55 c.993+3A>C Pathogenic ★ same condition
CEP55 p.Gln183Ter Likely pathogenic ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cep55-p-pro426arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown