Is ADAM15 p.Arg596Trp (c.1786C>T) pathogenic?

ADAM15 p.Arg596Trp (c.1786C>T) is classified Uncertain significance in ADAM15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.1062); Ultra-rare (popmax 0.0165%, mid).

How common is ADAM15 p.Arg596Trp (c.1786C>T) in the general population?

ADAM15 p.Arg596Trp (c.1786C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ADAM15 p.Arg596Trp (c.1786C>T)?

AlphaMissense predicts likely benign (score 0.1062) — an in-silico prediction, not a clinical call.

ADAM15 p.Arg596Trp

c.1786C>T · rs368562955 · VCV3144150

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1062	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -9.75	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 2.2	GERP 0.56, phastCons 0.025
Regional constraint	o/e 0.86	unconstrained · MANE · 11 kb · p 2.7e-06 · regional, not allelic
Overall
CADD	22.8	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

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00652%

Overall 0.00743% 120/1,614,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
South Asian	0.0132%	7,590
European (non-Finnish)	0.00839%	11,920
Remaining individualsnot grpmax-eligible	0.008%	12,502
African / African-American	0.004%	25,015

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.Arg596Trp
Coding: c.1786C>T
MANE Select: NM_207197
dbSNP: rs368562955
Type: single nucleotide variant
Location: chr1:155058310 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.35

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

Similar variants

ADAM15 p.Arg596Gln Likely benign ★ same residue
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

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-arg596trp (accessed [today's date]).

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