Is CRAT p.Pro41Ser (c.121C>T) pathogenic?

CRAT p.Pro41Ser (c.121C>T) is classified Uncertain significance in CRAT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-28). AlphaMissense: likely pathogenic (0.7861); Very rare (popmax 0.00111%, sas).

How common is CRAT p.Pro41Ser (c.121C>T) in the general population?

CRAT p.Pro41Ser (c.121C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about CRAT p.Pro41Ser (c.121C>T)?

AlphaMissense predicts likely pathogenic (score 0.7861) — an in-silico prediction, not a clinical call.

CRAT p.Pro41Ser

c.121C>T · rs775408401 · VCV1484776

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7861	likely pathogenic
REVEL	0.906	moderately pathogenic-leaning
SaProt	LLR -11.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 0.00046 · regional, not allelic
Overall
CADD	28.7	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 0.00111% South Asian · 1/90,250 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00025% 4/1,600,330 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,250
European (non-Finnish)	0.000255%	391,748

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.Pro41Ser
Coding: c.121C>T
MANE Select: NM_000755
dbSNP: rs775408401
Type: single nucleotide variant
Location: chr9:129107984 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.75 · 3 PDB

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

Similar variants

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
CRAT p.Ala604Val 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-pro41ser (accessed [today's date]).

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