Is CRYGA p.Arg15His (c.44G>A) pathogenic?

CRYGA p.Arg15His (c.44G>A) is classified Uncertain significance in CRYGA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-28). AlphaMissense: likely benign (0.0902); Ultra-rare (popmax 0.099%, mid).

How common is CRYGA p.Arg15His (c.44G>A) in the general population?

CRYGA p.Arg15His (c.44G>A) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about CRYGA p.Arg15His (c.44G>A)?

AlphaMissense predicts likely benign (score 0.0902) — an in-silico prediction, not a clinical call.

CRYGA p.Arg15His

c.44G>A · rs532100898 · VCV2400391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0902 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0902	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP 2.2, phastCons 0.96
Regional constraint	o/e 1.16	unconstrained · MANE · 2,749 bp · p 0.016 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.099% Middle Eastern · 6/6,062 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.00366% 59/1,613,728 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
South Asian	0.0307%	3,252
Admixed American	0.0117%	8,562
Remaining individualsnot grpmax-eligible	0.008%	12,499
Finnishnot grpmax-eligible	0.00625%	15,993
European (non-Finnish)	0.000763%	131,107

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: CRYGA
Protein: p.Arg15His
Coding: c.44G>A
MANE Select: NM_014617
dbSNP: rs532100898
Type: single nucleotide variant
Location: chr2:208163412 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.14
Residue 15: the beta/gamma crystallin 'greek key' 1 domain

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

Similar variants

CRYGA p.Arg99Ter Benign ★★ same type
CRYGA p.Ala110Thr Uncertain significance ★ ⚠ same type
CRYGA p.Arg140Gln Uncertain significance ★ ⚠ same type
CRYGA p.Arg140Leu Uncertain significance ★ ⚠ same type
CRYGA p.Arg142Gln Uncertain significance ★ ⚠ same type
CRYGA p.Arg153Ser Uncertain significance ★ ⚠ same type
CRYGA p.Arg169Gln Uncertain significance ★ ⚠ same type
CRYGA p.Arg169Trp 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/cryga-p-arg15his (accessed [today's date]).

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