Is CROT p.Ala104Val (c.311C>T) pathogenic?

CROT p.Ala104Val (c.311C>T) is classified Uncertain significance in CROT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: ambiguous (0.4356); Ultra-rare (popmax 0.0769%, sas).

How common is CROT p.Ala104Val (c.311C>T) in the general population?

CROT p.Ala104Val (c.311C>T) is ultra-rare (popmax 0.0769%, sas) (gnomAD).

What do computational predictors say about CROT p.Ala104Val (c.311C>T)?

AlphaMissense predicts ambiguous (score 0.4356) — an in-silico prediction, not a clinical call.

CROT p.Ala104Val

c.311C>T · rs773956752 · VCV2602683

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4356 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0769%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4356	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -7.56	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.072	GERP -0.84, phastCons 0.002
Regional constraint	o/e 0.98	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	15.19	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 0.0769% South Asian · 70/91,024 alleles

Filtering AF 0.0624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0571%

Overall 0.00595% 96/1,613,584 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0769%	1,300
Remaining individualsnot grpmax-eligible	0.008%	12,494
African / African-American	0.00534%	18,716
Admixed American	0.00334%	29,967
European (non-Finnish)	0.00127%	78,655

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: CROT
Protein: p.Ala104Val
Coding: c.311C>T
MANE Select: NM_021151
dbSNP: rs773956752
Type: single nucleotide variant
Location: chr7:87361460 (GRCh38)
Gene constraint: LOEUF 1.003 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.22

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

Similar variants

CROT c.116-1631C>T Uncertain significance ★ same type
CROT c.116-1651G>A Uncertain significance ★ same type
CROT c.116-1663C>A Uncertain significance ★ same type
CROT c.116-1686C>G Uncertain significance ★ same type
CROT p.Arg12Gln Uncertain significance ★ ⚠ same type
CROT p.Arg160Gln Uncertain significance ★ ⚠ same type
CROT p.Arg389Gly Uncertain significance ★ ⚠ same type
CROT p.Arg464Ser 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/crot-p-ala104val (accessed [today's date]).

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