Is COMMD8 p.Leu70Ser (c.209T>C) pathogenic?

COMMD8 p.Leu70Ser (c.209T>C) is classified Uncertain significance in COMMD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.1348); Absent from gnomAD v4.1.

How common is COMMD8 p.Leu70Ser (c.209T>C) in the general population?

COMMD8 p.Leu70Ser (c.209T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COMMD8 p.Leu70Ser (c.209T>C)?

AlphaMissense predicts likely benign (score 0.1348) — an in-silico prediction, not a clinical call.

COMMD8 p.Leu70Ser

c.209T>C · VCV4655805

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1348 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1348	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -9.27	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 5	GERP 0.56, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 12 kb · p 0.69 · regional, not allelic
Overall
CADD	14.97	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COMMD8
Protein: p.Leu70Ser
Coding: c.209T>C
MANE Select: NM_017845
Type: single nucleotide variant
Location: chr4:47460157 (GRCh38)
Gene constraint: LOEUF 1.369 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 3 PDB

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-leu70ser (accessed [today's date]).

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