Is CRYGA p.Arg153Ser (c.459G>T) pathogenic?

CRYGA p.Arg153Ser (c.459G>T) is classified Uncertain significance in CRYGA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.3018); Ultra-rare (popmax 0.012%, nfe).

How common is CRYGA p.Arg153Ser (c.459G>T) in the general population?

CRYGA p.Arg153Ser (c.459G>T) is ultra-rare (popmax 0.012%, nfe) (gnomAD).

What do computational predictors say about CRYGA p.Arg153Ser (c.459G>T)?

AlphaMissense predicts likely benign (score 0.3018) — an in-silico prediction, not a clinical call.

CRYGA p.Arg153Ser

c.459G>T · rs201293779 · VCV3077896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3018 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3018	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -5
Regional constraint	o/e 1.16	unconstrained · MANE · 2,749 bp · p 0.016 · regional, not allelic
Overall
CADD	14.46	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 0.012% European (non-Finnish) · 141/1,178,294 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00974%

Overall 0.00962% 155/1,612,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.012%	8,357
Remaining individualsnot grpmax-eligible	0.0112%	8,917
Admixed American	0.01%	9,999
East Asian	0.00223%	44,874

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.Arg153Ser
Coding: c.459G>T
MANE Select: NM_014617
dbSNP: rs201293779
Type: single nucleotide variant
Location: chr2:208160870 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.14
Residue 153: the beta/gamma crystallin 'greek key' 4 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.Arg15His 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-arg153ser (accessed [today's date]).

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