Is CENPC p.Met552Val (c.1654A>G) pathogenic?

CENPC p.Met552Val (c.1654A>G) is classified Likely benign in CENPC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.048); Ultra-rare (popmax 0.0165%, mid).

How common is CENPC p.Met552Val (c.1654A>G) in the general population?

CENPC p.Met552Val (c.1654A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CENPC p.Met552Val (c.1654A>G)?

AlphaMissense predicts likely benign (score 0.048) — an in-silico prediction, not a clinical call.

CENPC p.Met552Val

c.1654A>G · VCV4225556

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.048 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.048	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -4.37	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 -2	GERP -3.7
Regional constraint	o/e 0.91	unconstrained · MANE · 73 kb · p 0.0018 · regional, not allelic
Overall
CADD	0.02	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,054 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00174% 28/1,610,936 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
African / African-American	0.00534%	18,728
Admixed American	0.00335%	29,880
Remaining individualsnot grpmax-eligible	0.0032%	31,202
East Asian	0.00223%	44,830
European (non-Finnish)	0.00144%	69,370
South Asian	0.0011%	91,022

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: CENPC
Protein: p.Met552Val
Coding: c.1654A>G
MANE Select: NM_001812
Type: single nucleotide variant
Location: chr4:67509064 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 48.33 · 17 PDB
Residue 552: the 'disordered' region

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

Similar variants

CENPC p.Ala165Thr Uncertain significance ★ ⚠ same type
CENPC p.Ala23Val Uncertain significance ★ ⚠ same type
CENPC p.Ala313Val Uncertain significance ★ ⚠ same type
CENPC p.Ala324Thr Uncertain significance ★ ⚠ same type
CENPC p.Ala783Glu Uncertain significance ★ ⚠ same type
CENPC p.Ala783Thr Uncertain significance ★ ⚠ same type
CENPC p.Arg24His Uncertain significance ★ ⚠ same type
CENPC p.Arg272Gln Uncertain significance ★ ⚠ same type

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/cenpc-p-met552val (accessed [today's date]).

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