Is CRYM p.Ala254Val (c.761C>T) pathogenic?

CRYM p.Ala254Val (c.761C>T) is classified Conflicting classifications of pathogenicity in CRYM (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-18). AlphaMissense: ambiguous (0.3428); Ultra-rare (popmax 0.0217%, amr); Associated with autosomal dominant nonsyndromic hearing loss 40.

What condition is associated with CRYM p.Ala254Val (c.761C>T)?

CRYM p.Ala254Val (c.761C>T) is associated with autosomal dominant nonsyndromic hearing loss 40 (ClinVar).

How common is CRYM p.Ala254Val (c.761C>T) in the general population?

CRYM p.Ala254Val (c.761C>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about CRYM p.Ala254Val (c.761C>T)?

AlphaMissense predicts ambiguous (score 0.3428) — an in-silico prediction, not a clinical call.

CRYM p.Ala254Val

c.761C>T · rs727505275 · VCV179999

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3428 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

autosomal dominant nonsyndromic hearing loss 40

Computational evidence

Protein change
AlphaMissense	0.3428	ambiguous
REVEL	0.675	pathogenic-leaning
SaProt	LLR -10.60	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 19 kb · p 0.0044 · regional, not allelic
Overall
CADD	25.6	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 0.0217% Admixed American · 13/60,000 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000929% 15/1,613,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,615
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	74,908

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: CRYM
Protein: p.Ala254Val
Coding: c.761C>T
MANE Select: NM_001376256
dbSNP: rs727505275
Type: single nucleotide variant
Location: chr16:21262071 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.06 · 1 PDB
Residue 254: an α-helix

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

Disease context

autosomal dominant nonsyndromic hearing loss 40 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYM p.Ala254= Likely benign ★★ same residue
CRYM p.Val4Leu Uncertain significance ★★ ⚠ same condition
CRYM c.325-12T>C Benign ★★ same condition
CRYM p.Thr288= Benign ★★ same condition
CRYM p.Tyr247= Benign ★★ same condition
CRYM p.Ala10Gly Uncertain significance ★ ⚠ same condition
CRYM p.Ala303Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
CRYM p.Glu175Val Conflicting classifications of pathogenicity ★ ⚠ 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/crym-p-ala254val (accessed [today's date]).

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