Is CRYZ p.Ala2Pro (c.4G>C) pathogenic?

CRYZ p.Ala2Pro (c.4G>C) is classified Uncertain significance in CRYZ (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1304); Ultra-rare (popmax 0.0175%, afr).

How common is CRYZ p.Ala2Pro (c.4G>C) in the general population?

CRYZ p.Ala2Pro (c.4G>C) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

What do computational predictors say about CRYZ p.Ala2Pro (c.4G>C)?

AlphaMissense predicts likely benign (score 0.1304) — an in-silico prediction, not a clinical call.

CRYZ p.Ala2Pro

c.4G>C · VCV4656925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1304 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1304	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -9.50	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 1.3	GERP 0.71, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 19 kb · p 0.57 · regional, not allelic
Overall
CADD	22.7	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 0.0175% African / African-American · 13/74,246 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00819%

Overall 0.000876% 14/1,598,852 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0175%	5,711
Admixed American	0.00172%	58,298

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.Ala2Pro
Coding: c.4G>C
MANE Select: NM_001889
Type: single nucleotide variant
Location: chr1:74724818 (GRCh38)
Gene constraint: LOEUF 1.547 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.95 · 1 PDB
Residue 2: a modified residue (n-acetylalanine)

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.Arg138Gln Uncertain significance ★ ⚠ same type
CRYZ p.Arg138Gly Uncertain significance ★ ⚠ same type
CRYZ p.Arg242Gln 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-ala2pro (accessed [today's date]).

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