Is CRYAA p.Arg49His (c.146G>A) pathogenic?

CRYAA p.Arg49His (c.146G>A) is classified Uncertain significance in CRYAA (ClinVar, Single submitter, 1 submitter; last evaluated 2016-11-01). AlphaMissense: ambiguous (0.3923); Very rare (popmax 0.00476%, eas).

How common is CRYAA p.Arg49His (c.146G>A) in the general population?

CRYAA p.Arg49His (c.146G>A) is very rare (popmax 0.00476%, eas) (gnomAD).

What do computational predictors say about CRYAA p.Arg49His (c.146G>A)?

AlphaMissense predicts ambiguous (score 0.3923) — an in-silico prediction, not a clinical call.

CRYAA p.Arg49His

c.146G>A · rs754607706 · VCV809291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00476%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3923	ambiguous
REVEL	0.741	pathogenic-leaning
SaProt	LLR -9.06	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 0.35, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 3,177 bp · p 1.9e-11 · regional, not allelic
Overall
CADD	28.5	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 0.00476% East Asian · 2/41,986 alleles

Filtering AF 0.000789% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000295%

Overall 0.000649% 5/770,458 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00476%	20,993
European (non-Finnish)	0.000544%	183,673

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: CRYAA
Protein: p.Arg49His
Coding: c.146G>A
MANE Select: NM_000394
dbSNP: rs754607706
Type: single nucleotide variant
Location: chr21:43169245 (GRCh38)
Structure: AlphaFold pLDDT 74.60 · 5 PDB
Residue 49: a UniProt-annotated variant site (in ctrct9; uncertain significance); a UniProt-annotated variant site (in ctrct9); the 'required for complex formation with bfsp1 and bfsp2; during homooligomerization, mediates the association of 2 dimers to form a tetramer' region

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

Similar variants

CRYAA p.Arg49Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CRYAA p.Arg116Cys Pathogenic ★★ same type
CRYAA p.Arg116His Pathogenic ★★ same type
CRYAA p.Arg116Ser Pathogenic ★★ same type
CRYAA p.Arg12Cys Pathogenic/Likely pathogenic ★★ same type
CRYAA p.Arg21Gln Pathogenic ★★ ⚠ same type
CRYAA p.Arg21Trp Pathogenic/Likely pathogenic ★★ same type
CRYAA p.Arg54Cys Pathogenic/Likely pathogenic ★★ 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/cryaa-p-arg49his (accessed [today's date]).

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