Is ADAM15 p.Arg230Pro (c.689G>C) pathogenic?

ADAM15 p.Arg230Pro (c.689G>C) is classified Likely benign in ADAM15 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). AlphaMissense: likely benign (0.0599); Ultra-rare (popmax 0.0121%, sas).

How common is ADAM15 p.Arg230Pro (c.689G>C) in the general population?

ADAM15 p.Arg230Pro (c.689G>C) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about ADAM15 p.Arg230Pro (c.689G>C)?

AlphaMissense predicts likely benign (score 0.0599) — an in-silico prediction, not a clinical call.

ADAM15 p.Arg230Pro

c.689G>C · rs753684580 · VCV3144226

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0599 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0599	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -3.42	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 0.64	GERP -3.5, phastCons 0.092
Regional constraint	o/e 0.86	unconstrained · MANE · 11 kb · p 2.7e-06 · regional, not allelic
Overall
CADD	1.902	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 0.0121% South Asian · 11/91,080 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000744% 12/1,613,928 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,280
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: ADAM15
Protein: p.Arg230Pro
Coding: c.689G>C
MANE Select: NM_207197
dbSNP: rs753684580
Type: single nucleotide variant
Location: chr1:155055945 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.35
Residue 230: 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-arg230pro (accessed [today's date]).

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