Is CROT p.Arg464Ser (c.1392G>C) pathogenic?

CROT p.Arg464Ser (c.1392G>C) is classified Uncertain significance in CROT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1051); Absent from gnomAD v4.1.

How common is CROT p.Arg464Ser (c.1392G>C) in the general population?

CROT p.Arg464Ser (c.1392G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CROT p.Arg464Ser (c.1392G>C)?

AlphaMissense predicts likely benign (score 0.1051) — an in-silico prediction, not a clinical call.

CROT p.Arg464Ser

c.1392G>C · VCV4234456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1051 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1051	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -4.68	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 -3.5	GERP -1.2
Regional constraint	o/e 0.98	unconstrained · MANE · 50 kb · p 0.53 · regional, not allelic
Overall
CADD	3.347	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CROT
Protein: p.Arg464Ser
Coding: c.1392G>C
MANE Select: NM_021151
Type: single nucleotide variant
Location: chr7:87391679 (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.Ala104Val 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

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-arg464ser (accessed [today's date]).

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