Is CRYGC p.Arg48His (c.143G>A) pathogenic?

CRYGC p.Arg48His (c.143G>A) is classified Benign in CRYGC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1044); Common (popmax 5.09%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Usher syndrome type 2C.

What condition is associated with CRYGC p.Arg48His (c.143G>A)?

CRYGC p.Arg48His (c.143G>A) is associated with Usher syndrome type 2C (ClinVar).

What do computational predictors say about CRYGC p.Arg48His (c.143G>A)?

AlphaMissense predicts likely benign (score 0.1044) — an in-silico prediction, not a clinical call.

CRYGC p.Arg48His

Q: How common is CRYGC p.Arg48His (c.143G>A) in the general population?

CRYGC p.Arg48His (c.143G>A) is common (popmax 5.09%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.143G>A · rs61751949 · VCV402565

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1044 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.09%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 2C

Computational evidence

Protein change
AlphaMissense	0.1044	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -7.77	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 -1.2	GERP -2.5
Regional constraint	o/e 1.00	unconstrained · MANE · 1,586 bp · p 0.96 · regional, not allelic
Overall
CADD	18.05	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.09% South Asian · 4,639/91,080 alleles

Filtering AF 4.97% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.92%

Overall 1.69% 27,332/1,614,176 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	5.09%	20
Finnishnot grpmax-eligible	1.73%	58
European (non-Finnish)	1.68%	60
Remaining individualsnot grpmax-eligible	1.59%	63
Middle Eastern	1.44%	70
Admixed American	0.675%	148
Ashkenazi Jewishnot grpmax-eligible	0.348%	287
African / African-American	0.272%	368
Amishnot grpmax-eligible	0.22%	455
East Asian	0.0111%	8,976

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: CRYGC
Protein: p.Arg48His
Coding: c.143G>A
MANE Select: NM_020989
dbSNP: rs61751949
Type: single nucleotide variant
Location: chr2:208129550 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 96.66 · 1 PDB
Residue 48: a UniProt-annotated variant site (in); a β-strand; the beta/gamma crystallin 'greek key' 2 domain

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

Disease context

Usher syndrome type 2C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYGC p.Arg48Cys Uncertain significance ★ ⚠ same residue
CRYGC p.Trp157Ter Pathogenic/Likely pathogenic ★★ same type
CRYGC p.Arg122His Uncertain significance ★★ ⚠ same type
CRYGC p.Arg15His Uncertain significance ★★ ⚠ same type
CRYGC p.Arg77Cys Uncertain significance ★★ ⚠ same type
CRYGC p.Arg77His Uncertain significance ★★ ⚠ same type
CRYGC p.Asn138Ser Uncertain significance ★★ ⚠ same type
CRYGC p.Glu150Asp 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/crygc-p-arg48his (accessed [today's date]).

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