Is CRYM p.Ala254= (c.762C>T) pathogenic?

CRYM p.Ala254= (c.762C>T) is classified Likely benign in CRYM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-20). Rare (popmax 0.143%, eas).

How common is CRYM p.Ala254= (c.762C>T) in the general population?

CRYM p.Ala254= (c.762C>T) is rare (popmax 0.143%, eas) (gnomAD).

CRYM p.Ala254=

c.762C>T · rs576361852 · VCV1317752

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.143%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -3, phastCons 0.84
Overall
CADD	7.474	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.143% East Asian · 64/44,872 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.104%

Overall 0.00465% 75/1,614,032 alleles · rare exomes 64/1,461,826 · genomes 11/152,206 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.143%	701
Remaining individualsnot grpmax-eligible	0.0176%	5,682

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: CRYM
Protein: p.Ala254=
Coding: c.762C>T
MANE Select: NM_001376256
dbSNP: rs576361852
Type: single nucleotide variant
Location: chr16:21262070 (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

Similar variants

CRYM p.Ala254Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CRYM p.Ala178Glu Uncertain significance ★★ ⚠ same type
CRYM p.Glu172Gly Uncertain significance ★★ ⚠ same type
CRYM p.Leu72Val Uncertain significance ★★ ⚠ same type
CRYM p.Met295Ile Uncertain significance ★★ ⚠ same type
CRYM p.Thr95Ser Uncertain significance ★★ ⚠ same type
CRYM p.Val4Leu Uncertain significance ★★ ⚠ same type
CRYM c.171-118C>T Benign ★★ 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/crym-p-ala254 (accessed [today's date]).

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