Is CRYL1 p.Arg231Trp (c.691C>T) pathogenic?

CRYL1 p.Arg231Trp (c.691C>T) is classified Uncertain significance in CRYL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.8171); Very rare (popmax 0.00533%, afr).

How common is CRYL1 p.Arg231Trp (c.691C>T) in the general population?

CRYL1 p.Arg231Trp (c.691C>T) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about CRYL1 p.Arg231Trp (c.691C>T)?

AlphaMissense predicts likely pathogenic (score 0.8171) — an in-silico prediction, not a clinical call.

CRYL1 p.Arg231Trp

c.691C>T · rs747863623 · VCV3077922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8171 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8171	likely pathogenic
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -10.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 122 kb · p 0.88 · regional, not allelic
Overall
CADD	33.0	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 0.00533% African / African-American · 4/75,002 alleles

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

Overall 0.00118% 19/1,613,576 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,751
Admixed American	0.00501%	19,973
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.000932%	107,249

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: CRYL1
Protein: p.Arg231Trp
Coding: c.691C>T
MANE Select: NM_015974
dbSNP: rs747863623
Type: single nucleotide variant
Location: chr13:20413330 (GRCh38)
Gene constraint: LOEUF 1.297 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.66 · 1 PDB
Residue 231: an α-helix

Full CRYL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRYL1 c.149+24A>G Benign ★★ same type
CRYL1 c.276+13C>T Benign ★★ same type
CRYL1 c.41+65T>G Benign ★★ same type
CRYL1 c.438+49G>T Benign ★★ same type
CRYL1 c.438+62C>T Benign ★★ same type
CRYL1 c.439-40A>G Benign ★★ same type
CRYL1 c.634-202T>C Benign ★★ same type
CRYL1 c.846+110A>G 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/cryl1-p-arg231trp (accessed [today's date]).

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