Is COMMD8 p.Leu9Trp (c.26T>G) pathogenic?

COMMD8 p.Leu9Trp (c.26T>G) is classified Uncertain significance in COMMD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: ambiguous (0.3478); Ultra-rare (popmax 0.0548%, sas).

How common is COMMD8 p.Leu9Trp (c.26T>G) in the general population?

COMMD8 p.Leu9Trp (c.26T>G) is ultra-rare (popmax 0.0548%, sas) (gnomAD).

What do computational predictors say about COMMD8 p.Leu9Trp (c.26T>G)?

AlphaMissense predicts ambiguous (score 0.3478) — an in-silico prediction, not a clinical call.

COMMD8 p.Leu9Trp

c.26T>G · VCV4005705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3478 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0548%, sas)

Computational evidence

Protein change
AlphaMissense	0.3478	ambiguous
REVEL	0.303	indeterminate
SaProt	LLR -7.78	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 12 kb · p 0.69 · regional, not allelic
Overall
CADD	26.1	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 0.0548% South Asian · 46/83,932 alleles

Filtering AF 0.0422% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0377%

Overall 0.00323% 50/1,549,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0548%	1,825
Remaining individualsnot grpmax-eligible	0.005%	19,999
European (non-Finnish)	8.72e-05%	1,146,385

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: COMMD8
Protein: p.Leu9Trp
Coding: c.26T>G
MANE Select: NM_017845
Type: single nucleotide variant
Location: chr4:47463626 (GRCh38)
Gene constraint: LOEUF 1.369 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 3 PDB
Residue 9: an α-helix

Full COMMD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COMMD8 p.Leu9Ter Uncertain significance ★ same residue
COMMD8 p.Trp122Gly Uncertain significance ★★ ⚠ same type
COMMD8 p.Arg11Gln Uncertain significance ★ ⚠ same type
COMMD8 p.Arg97Gly Uncertain significance ★ same type
COMMD8 p.Asp131Glu Uncertain significance ★ ⚠ same type
COMMD8 p.Gln116Arg Uncertain significance ★ ⚠ same type
COMMD8 p.Glu108Asp Uncertain significance ★ ⚠ same type
COMMD8 p.Glu164Gly 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/commd8-p-leu9trp (accessed [today's date]).

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