Is CRAT p.Ala260Pro (c.778G>C) pathogenic?

CRAT p.Ala260Pro (c.778G>C) is classified Uncertain significance in CRAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.9808); Very rare (popmax 0.00167%, amr).

How common is CRAT p.Ala260Pro (c.778G>C) in the general population?

CRAT p.Ala260Pro (c.778G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CRAT p.Ala260Pro (c.778G>C)?

AlphaMissense predicts likely pathogenic (score 0.9808) — an in-silico prediction, not a clinical call.

CRAT p.Ala260Pro

c.778G>C · rs763477667 · VCV2114583

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9808	likely pathogenic · top 7% in CRAT
REVEL	0.556	indeterminate
SaProt	LLR -16.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 0.00046 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/60,008 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,714 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,008
European (non-Finnish)	0.000169%	589,998

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.Ala260Pro
Coding: c.778G>C
MANE Select: NM_000755
dbSNP: rs763477667
Type: single nucleotide variant
Location: chr9:129101910 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.75 · 3 PDB
Residue 260: an α-helix

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

Similar variants

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CRAT p.Ala596Thr Uncertain significance ★★ ⚠ same type
CRAT p.Ala596Val Uncertain significance ★★ ⚠ same type
CRAT p.Ala600Thr Uncertain significance ★★ ⚠ same type
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CRAT p.Arg111His 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-ala260pro (accessed [today's date]).

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