Is COMMD8 p.Ser113Phe (c.338C>T) pathogenic?

COMMD8 p.Ser113Phe (c.338C>T) is classified Uncertain significance in COMMD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.6318); Ultra-rare (popmax 0.0919%, sas).

How common is COMMD8 p.Ser113Phe (c.338C>T) in the general population?

COMMD8 p.Ser113Phe (c.338C>T) is ultra-rare (popmax 0.0919%, sas) (gnomAD).

What do computational predictors say about COMMD8 p.Ser113Phe (c.338C>T)?

AlphaMissense predicts likely pathogenic (score 0.6318) — an in-silico prediction, not a clinical call.

COMMD8 p.Ser113Phe

c.338C>T · VCV4655803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6318 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0919%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6318	likely pathogenic
REVEL	0.394	indeterminate
SaProt	LLR -11.49	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 12 kb · p 0.69 · regional, not allelic
Overall
CADD	28.1	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 0.0919% South Asian · 83/90,310 alleles

Filtering AF 0.0759% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.07%

Overall 0.00615% 99/1,609,468 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0919%	1,088
Middle Eastern	0.0331%	3,021
Remaining individualsnot grpmax-eligible	0.0128%	7,786
East Asian	0.00225%	44,402
European (non-Finnish)	0.000424%	235,662

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.Ser113Phe
Coding: c.338C>T
MANE Select: NM_017845
Type: single nucleotide variant
Location: chr4:47456614 (GRCh38)
Gene constraint: LOEUF 1.369 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 3 PDB
Residue 113: a β-strand

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

Similar variants

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
COMMD8 p.Glu47Val 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-ser113phe (accessed [today's date]).

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