Is CRYM p.Val89Asp (c.266T>A) pathogenic?

CRYM p.Val89Asp (c.266T>A) is classified Uncertain significance in CRYM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely benign (0.214); Very rare (popmax 0.000169%, nfe).

How common is CRYM p.Val89Asp (c.266T>A) in the general population?

CRYM p.Val89Asp (c.266T>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CRYM p.Val89Asp (c.266T>A)?

AlphaMissense predicts likely benign (score 0.214) — an in-silico prediction, not a clinical call.

CRYM p.Val89Asp

c.266T>A · rs975545045 · VCV2257098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.214 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.214	likely benign
REVEL	0.528	indeterminate
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.11	GERP -3.4
Regional constraint	o/e 0.86	unconstrained · MANE · 19 kb · p 0.0044 · regional, not allelic
Overall
CADD	20.8	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 0.000169% European (non-Finnish) · 2/1,179,986 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,702 alleles · very rare exomes 1/1,461,656 · genomes 1/152,046 · joint denominator

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.Val89Asp
Coding: c.266T>A
MANE Select: NM_001376256
dbSNP: rs975545045
Type: single nucleotide variant
Location: chr16:21277489 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.06 · 1 PDB
Residue 89: a β-strand

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

Similar variants

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
CRYM c.171-19G>A Likely 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-val89asp (accessed [today's date]).

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