Is ADAM15 p.Ser336Pro (c.1006T>C) pathogenic?

ADAM15 p.Ser336Pro (c.1006T>C) is classified Uncertain significance in ADAM15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: likely pathogenic (0.9138); Absent from gnomAD v4.1.

How common is ADAM15 p.Ser336Pro (c.1006T>C) in the general population?

ADAM15 p.Ser336Pro (c.1006T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAM15 p.Ser336Pro (c.1006T>C)?

AlphaMissense predicts likely pathogenic (score 0.9138) — an in-silico prediction, not a clinical call.

ADAM15 p.Ser336Pro

c.1006T>C · rs2102405216 · VCV3144099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9138 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,560,032)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9138	likely pathogenic · top 5% in ADAM15
REVEL	0.252	benign-leaning
SaProt	LLR -11.84	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.2	GERP -1.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 11 kb · p 2.7e-06 · regional, not allelic
Overall
CADD	23.4	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

No allele count reported in gnomAD v4.1 (AN 1,560,032). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ADAM15
Protein: p.Ser336Pro
Coding: c.1006T>C
MANE Select: NM_207197
dbSNP: rs2102405216
Type: single nucleotide variant
Location: chr1:155056959 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.35
Residue 336: a disulfide bond; the peptidase m12b domain

Full ADAM15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM15 c.1918-6G>T Benign ★★ same type
ADAM15 p.Arg268His Likely benign ★★ ⚠ same type
ADAM15 p.Leu240Met Benign ★★ same type
ADAM15 p.Ala221Asp Uncertain significance ★ ⚠ same type
ADAM15 p.Ala301Val Uncertain significance ★ ⚠ same type
ADAM15 p.Ala343Thr Uncertain significance ★ ⚠ same type
ADAM15 p.Ala347Ser Uncertain significance ★ ⚠ same type
ADAM15 p.Ala39Thr 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/adam15-p-ser336pro (accessed [today's date]).

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