Is ADAM9 p.Cys656Ser (c.1966T>A) pathogenic?

ADAM9 p.Cys656Ser (c.1966T>A) is classified Uncertain significance in ADAM9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-20). AlphaMissense: likely pathogenic (0.9976); Absent from gnomAD v4.1.

How common is ADAM9 p.Cys656Ser (c.1966T>A) in the general population?

ADAM9 p.Cys656Ser (c.1966T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAM9 p.Cys656Ser (c.1966T>A)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

ADAM9 p.Cys656Ser

c.1966T>A · rs2536378694 · VCV2128226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic · top 3% in ADAM9
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.56	acceptor loss, 3 bp away · masked 0 · deltas
Pangolin	Δ0.52	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 26 kb · p 0.88 · regional, not allelic
Overall
CADD	25.6	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

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: ADAM9
Protein: p.Cys656Ser
Coding: c.1966T>A
MANE Select: NM_003816
dbSNP: rs2536378694
Type: single nucleotide variant
Location: chr8:39082971 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.14
Residue 656: a disulfide bond; the egf-like domain

Full ADAM9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM9 p.Cys656Ter Pathogenic ★ same residue
ADAM9 p.Cys656Tyr Uncertain significance ★ ⚠ same residue
ADAM9 p.Tyr213Ter Pathogenic/Likely pathogenic ★★ same type
ADAM9 c.195+5G>A Uncertain significance ★★ same type
ADAM9 c.997-3C>G Uncertain significance ★★ same type
ADAM9 p.Ala145Glu Uncertain significance ★★ ⚠ same type
ADAM9 p.Ala424Thr Uncertain significance ★★ ⚠ same type
ADAM9 p.Ala510Thr 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/adam9-p-cys656ser (accessed [today's date]).

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