Is CRYZ p.His239Arg (c.716A>G) pathogenic?

CRYZ p.His239Arg (c.716A>G) is classified Uncertain significance in CRYZ (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: likely benign (0.0604); Very rare (popmax 0.0092%, amr).

How common is CRYZ p.His239Arg (c.716A>G) in the general population?

CRYZ p.His239Arg (c.716A>G) is very rare (popmax 0.0092%, amr) (gnomAD).

What do computational predictors say about CRYZ p.His239Arg (c.716A>G)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

CRYZ p.His239Arg

c.716A>G · rs746430316 · VCV3077930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0092%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -4.21	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 -6.1	GERP -5.3
Regional constraint	o/e 1.03	unconstrained · MANE · 19 kb · p 0.57 · regional, not allelic
Overall
CADD	0.012	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 0.0092% Admixed American · 5/54,376 alleles

Filtering AF 0.00353% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00235%

Overall 0.000568% 9/1,584,190 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0092%	10,875
Remaining individualsnot grpmax-eligible	0.00489%	20,438
European (non-Finnish)	8.58e-05%	1,165,618

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: CRYZ
Protein: p.His239Arg
Coding: c.716A>G
MANE Select: NM_001889
dbSNP: rs746430316
Type: single nucleotide variant
Location: chr1:74707119 (GRCh38)
Gene constraint: LOEUF 1.547 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.95 · 1 PDB
Residue 239: a β-strand

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

Similar variants

CRYZ c.265-1G>A Likely benign ★★ same type
CRYZ p.Glu183Lys Benign ★★ ⚠ same type
CRYZ p.Ala139Thr Uncertain significance ★ ⚠ same type
CRYZ p.Ala148Val Uncertain significance ★ ⚠ same type
CRYZ p.Ala164Thr Uncertain significance ★ ⚠ same type
CRYZ p.Ala2Pro Uncertain significance ★ ⚠ same type
CRYZ p.Arg138Gln Uncertain significance ★ ⚠ same type
CRYZ p.Arg138Gly 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/cryz-p-his239arg (accessed [today's date]).

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