Is GCOM1 p.Leu433Pro (c.1298T>C) pathogenic?

GCOM1 p.Leu433Pro (c.1298T>C) is classified Uncertain significance in GCOM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-21). AlphaMissense: likely benign (0.079); Ultra-rare (popmax 0.0668%, mid); Associated with Inborn genetic diseases.

What condition is associated with GCOM1 p.Leu433Pro (c.1298T>C)?

GCOM1 p.Leu433Pro (c.1298T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GCOM1 p.Leu433Pro (c.1298T>C) in the general population?

GCOM1 p.Leu433Pro (c.1298T>C) is ultra-rare (popmax 0.0668%, mid) (gnomAD).

What do computational predictors say about GCOM1 p.Leu433Pro (c.1298T>C)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

GCOM1 p.Leu433Pro

c.1298T>C · rs374448189 · VCV2513018

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -6.37	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 1.5	GERP 6, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 92 kb · p 0.02 · regional, not allelic
Overall
CADD	19.94	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

Grpmax group 0.0668% Middle Eastern · 4/5,986 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0135% 215/1,597,868 alleles · ultra-rare exomes 199/1,448,350 · genomes 16/149,518 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0668%	1,496
South Asian	0.0196%	5,108
European (non-Finnish)	0.0154%	6,494
Finnishnot grpmax-eligible	0.00787%	12,704
Admixed American	0.00713%	14,033
Remaining individualsnot grpmax-eligible	0.00645%	15,492

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: GCOM1
Protein: p.Leu433Pro
Coding: c.1298T>C
dbSNP: rs374448189
Type: single nucleotide variant
Location: chr15:57675062 (GRCh38)
Gene constraint: LOEUF 1.129 · pLI <0.01 (gnomAD)

Full GCOM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GCOM1 p.Ala109Thr Uncertain significance ★ ⚠ same condition
GCOM1 p.Ala168Val Uncertain significance ★ ⚠ same condition
GCOM1 p.Ala16Val Uncertain significance ★ ⚠ same condition
GCOM1 p.Ala288Thr Uncertain significance ★ ⚠ same condition
GCOM1 p.Ala345Ser Uncertain significance ★ ⚠ same condition
GCOM1 p.Arg108Thr Uncertain significance ★ ⚠ same condition
GCOM1 p.Arg117Gln Uncertain significance ★ ⚠ same condition
GCOM1 p.Arg130Leu Uncertain significance ★ ⚠ same condition

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/gcom1-p-leu433pro (accessed [today's date]).

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