Is CENPH p.Leu44Pro (c.131T>C) pathogenic?

CENPH p.Leu44Pro (c.131T>C) is classified Uncertain significance in CENPH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely pathogenic (0.6281); Ultra-rare (popmax 0.0175%, eas).

How common is CENPH p.Leu44Pro (c.131T>C) in the general population?

CENPH p.Leu44Pro (c.131T>C) is ultra-rare (popmax 0.0175%, eas) (gnomAD).

What do computational predictors say about CENPH p.Leu44Pro (c.131T>C)?

AlphaMissense predicts likely pathogenic (score 0.6281) — an in-silico prediction, not a clinical call.

CENPH p.Leu44Pro

c.131T>C · VCV3490361

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6281 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6281	likely pathogenic · top 7% in CENPH
REVEL	0.426	indeterminate
SaProt	LLR -12.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 20 kb · p 0.6 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0175% East Asian · 7/39,924 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00576%

Overall 0.000535% 8/1,496,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0175%	5,703
Remaining individualsnot grpmax-eligible	0.00173%	57,682

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: CENPH
Protein: p.Leu44Pro
Coding: c.131T>C
MANE Select: NM_022909
Type: single nucleotide variant
Location: chr5:69189765 (GRCh38)
Gene constraint: LOEUF 1.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.95 · 13 PDB
Residue 44: an α-helix

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

Similar variants

CENPH p.Ala22Gly Uncertain significance ★ ⚠ same type
CENPH p.Ala33Val Uncertain significance ★ ⚠ same type
CENPH p.Ala48Thr Uncertain significance ★ ⚠ same type
CENPH p.Arg21Trp Uncertain significance ★ ⚠ same type
CENPH p.Arg39His Uncertain significance ★ ⚠ same type
CENPH p.Arg47Thr Uncertain significance ★ ⚠ same type
CENPH p.Asp128Gly Uncertain significance ★ ⚠ same type
CENPH p.Asp38Glu 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/cenph-p-leu44pro (accessed [today's date]).

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