Is CRAT p.Asp508His (c.1522G>C) pathogenic?

CRAT p.Asp508His (c.1522G>C) is classified Uncertain significance in CRAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: ambiguous (0.4831); Ultra-rare (popmax 0.0188%, eas).

How common is CRAT p.Asp508His (c.1522G>C) in the general population?

CRAT p.Asp508His (c.1522G>C) is ultra-rare (popmax 0.0188%, eas) (gnomAD).

What do computational predictors say about CRAT p.Asp508His (c.1522G>C)?

AlphaMissense predicts ambiguous (score 0.4831) — an in-silico prediction, not a clinical call.

CRAT p.Asp508His

c.1522G>C · rs764225834 · VCV2714710

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4831 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, eas)

Computational evidence

Protein change
AlphaMissense	0.4831	ambiguous
REVEL	0.576	indeterminate
SaProt	LLR -8.49	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.42, phastCons 0.92
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 0.00046 · regional, not allelic
Overall
CADD	15.42	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 0.0188% East Asian · 8/42,634 alleles

Filtering AF 0.00934% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0068%

Overall 0.000641% 10/1,559,304 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0188%	5,329
Remaining individualsnot grpmax-eligible	0.00331%	30,224

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: CRAT
Protein: p.Asp508His
Coding: c.1522G>C
MANE Select: NM_000755
dbSNP: rs764225834
Type: single nucleotide variant
Location: chr9:129097255 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.75 · 3 PDB
Residue 508: an α-helix

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

Similar variants

CRAT p.Asp508Asn Uncertain significance ★★ ⚠ same residue
CRAT p.Ala260Pro Uncertain significance ★★ ⚠ same type
CRAT p.Ala262Thr Uncertain significance ★★ ⚠ same type
CRAT p.Ala544Thr Uncertain significance ★★ ⚠ same type
CRAT p.Ala546Thr Uncertain significance ★★ ⚠ same type
CRAT p.Ala596Thr Uncertain significance ★★ ⚠ same type
CRAT p.Ala596Val Uncertain significance ★★ ⚠ same type
CRAT p.Ala600Thr 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/crat-p-asp508his (accessed [today's date]).

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