Is CRYGS p.Ser129Phe (c.386C>T) pathogenic?

CRYGS p.Ser129Phe (c.386C>T) is classified Uncertain significance in CRYGS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: likely pathogenic (0.9724); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRYGS p.Ser129Phe (c.386C>T)?

CRYGS p.Ser129Phe (c.386C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRYGS p.Ser129Phe (c.386C>T) in the general population?

CRYGS p.Ser129Phe (c.386C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CRYGS p.Ser129Phe (c.386C>T)?

AlphaMissense predicts likely pathogenic (score 0.9724) — an in-silico prediction, not a clinical call.

CRYGS p.Ser129Phe

c.386C>T · rs780713400 · VCV3077913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9724 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9724	likely pathogenic · top 5% in CRYGS
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -16.30	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 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 5,627 bp · p 0.1 · regional, not allelic
Overall
CADD	27.0	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 0.00267% African / African-American · 2/74,900 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,994 alleles · very rare exomes 2/1,461,866 · genomes 1/152,128 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,450
European (non-Finnish)	8.47e-05%	1,180,038

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: CRYGS
Protein: p.Ser129Phe
Coding: c.386C>T
MANE Select: NM_017541
dbSNP: rs780713400
Type: single nucleotide variant
Location: chr3:186538847 (GRCh38)
Gene constraint: LOEUF 0.881 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 95.63 · 12 PDB
Residue 129: the beta/gamma crystallin 'greek key' 3 domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYGS p.Arg174Cys Uncertain significance ★★ ⚠ same condition
CRYGS p.Arg158Gln Uncertain significance ★ ⚠ same condition
CRYGS p.Arg174His Uncertain significance ★ ⚠ same condition
CRYGS p.Arg174Ser Uncertain significance ★ ⚠ same condition
CRYGS p.Arg175Cys Uncertain significance ★ ⚠ same condition
CRYGS p.Arg19Cys Uncertain significance ★ same condition
CRYGS p.Arg19His Uncertain significance ★ ⚠ same condition
CRYGS p.Arg72Cys Uncertain significance ★ ⚠ same condition

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/crygs-p-ser129phe (accessed [today's date]).

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