Is COMMD1 p.Ile138Met (c.414A>G) pathogenic?

COMMD1 p.Ile138Met (c.414A>G) is classified Uncertain significance in COMMD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.0841); Very rare (popmax 0.00833%, amr).

How common is COMMD1 p.Ile138Met (c.414A>G) in the general population?

COMMD1 p.Ile138Met (c.414A>G) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about COMMD1 p.Ile138Met (c.414A>G)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

COMMD1 p.Ile138Met

c.414A>G · rs550878902 · VCV2396646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -6.91	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 1.7	GERP -3.7, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 230 kb · p 0.012 · regional, not allelic
Overall
CADD	17.88	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 0.00833% Admixed American · 5/60,010 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000681% 11/1,614,128 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,002
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000424%	236,007

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: COMMD1
Protein: p.Ile138Met
Coding: c.414A>G
MANE Select: NM_152516
dbSNP: rs550878902
Type: single nucleotide variant
Location: chr2:62000934 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.58 · 4 PDB
Residue 138: the comm domain; the 'required for binding to ptdins(4,5)p2' region

Full COMMD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMMD1 p.Asn111Ile Uncertain significance ★ ⚠ same type
COMMD1 p.Asn190Asp Uncertain significance ★ ⚠ same type
COMMD1 p.Gln131His Uncertain significance ★ ⚠ same type
COMMD1 p.Gln137Glu Uncertain significance ★ ⚠ same type
COMMD1 p.Glu148Asp Uncertain significance ★ ⚠ same type
COMMD1 p.Glu33Val Uncertain significance ★ ⚠ same type
COMMD1 p.Glu5Asp Uncertain significance ★ ⚠ same type
COMMD1 p.Gly121Asp 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/commd1-p-ile138met (accessed [today's date]).

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