Is COMMD2 p.Leu75Pro (c.224T>C) pathogenic?

COMMD2 p.Leu75Pro (c.224T>C) is classified Uncertain significance in COMMD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-26). AlphaMissense: likely pathogenic (0.9175); Very rare (popmax 0.00801%, afr).

How common is COMMD2 p.Leu75Pro (c.224T>C) in the general population?

COMMD2 p.Leu75Pro (c.224T>C) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about COMMD2 p.Leu75Pro (c.224T>C)?

AlphaMissense predicts likely pathogenic (score 0.9175) — an in-silico prediction, not a clinical call.

COMMD2 p.Leu75Pro

c.224T>C · VCV3495892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9175 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9175	likely pathogenic
REVEL	0.457	indeterminate
SaProt	LLR -10.75	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.52 · regional, not allelic
Overall
CADD	27.5	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 0.00801% African / African-American · 6/74,924 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000372% 6/1,613,982 alleles · very rare

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: COMMD2
Protein: p.Leu75Pro
Coding: c.224T>C
MANE Select: NM_016094
Type: single nucleotide variant
Location: chr3:149751407 (GRCh38)
Gene constraint: LOEUF 1.611 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.00 · 3 PDB
Residue 75: an α-helix

Full COMMD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMMD2 p.Ala118Val Uncertain significance ★ ⚠ same type
COMMD2 p.Ala136Thr Uncertain significance ★ ⚠ same type
COMMD2 p.Ala170Thr Uncertain significance ★ ⚠ same type
COMMD2 p.Arg130Gln Uncertain significance ★ ⚠ same type
COMMD2 p.Arg196His Uncertain significance ★ ⚠ same type
COMMD2 p.Arg196Leu Uncertain significance ★ ⚠ same type
COMMD2 p.Arg29Leu Uncertain significance ★ ⚠ same type
COMMD2 p.Arg29Trp 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/commd2-p-leu75pro (accessed [today's date]).

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