Is CRYGA p.Arg99Ter (c.295C>T) pathogenic?

CRYGA p.Arg99Ter (c.295C>T) is classified Benign in CRYGA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). Low-frequency (popmax 2.38%, amr).

How common is CRYGA p.Arg99Ter (c.295C>T) in the general population?

CRYGA p.Arg99Ter (c.295C>T) is low-frequency (popmax 2.38%, amr) (gnomAD).

CRYGA p.Arg99Ter

c.295C>T · rs116344874 · VCV709075

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 2.38%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.30	gain · loss 0.30 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -1.3	GERP -5
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.38% Admixed American · 1,431/60,006 alleles

Filtering AF 2.28% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.24%

Overall 0.103% 1,667/1,614,074 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	2.38%	42
East Asian	0.127%	787
Remaining individualsnot grpmax-eligible	0.114%	880
African / African-American	0.0293%	3,410
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0072%	13,882

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.Arg99Ter
Coding: c.295C>T
MANE Select: NM_014617
dbSNP: rs116344874
Type: single nucleotide variant
Location: chr2:208161034 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.14
Residue 99: the beta/gamma crystallin 'greek key' 3 domain

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

Similar variants

CRYGA p.Arg99Gln Uncertain significance ★ ⚠ same residue
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.Arg15His Uncertain significance ★ ⚠ same type
CRYGA p.Arg169Gln 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-arg99ter (accessed [today's date]).

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