Is ADAM18 p.Cys360Phe (c.1079G>T) pathogenic?

ADAM18 p.Cys360Phe (c.1079G>T) is classified Uncertain significance in ADAM18 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely pathogenic (0.7269); Very rare (popmax 0.00687%, amr).

How common is ADAM18 p.Cys360Phe (c.1079G>T) in the general population?

ADAM18 p.Cys360Phe (c.1079G>T) is very rare (popmax 0.00687%, amr) (gnomAD).

What do computational predictors say about ADAM18 p.Cys360Phe (c.1079G>T)?

AlphaMissense predicts likely pathogenic (score 0.7269) — an in-silico prediction, not a clinical call.

ADAM18 p.Cys360Phe

c.1079G>T · VCV3486704

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7269 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00687%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7269	likely pathogenic · top 9% in ADAM18
REVEL	0.52	indeterminate
SaProt	LLR -14.83	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 145 kb · p 0.059 · regional, not allelic
Overall
CADD	24.1	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

Grpmax group 0.00687% Admixed American · 4/58,256 alleles

Filtering AF 0.0023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00138%

Overall 0.000623% 10/1,604,248 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00687%	14,564
Remaining individualsnot grpmax-eligible	0.00483%	20,709
African / African-American	0.00268%	37,244
European (non-Finnish)	8.5e-05%	1,175,825

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: ADAM18
Protein: p.Cys360Phe
Coding: c.1079G>T
MANE Select: NM_014237
Type: single nucleotide variant
Location: chr8:39648376 (GRCh38)
Gene constraint: LOEUF 1.585 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.24
Residue 360: a disulfide bond; the peptidase m12b domain

Full ADAM18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM18 p.Ala249Thr Uncertain significance ★ ⚠ same type
ADAM18 p.Ala258Glu Uncertain significance ★ ⚠ same type
ADAM18 p.Ala340Thr Uncertain significance ★ ⚠ same type
ADAM18 p.Ala340Val Uncertain significance ★ ⚠ same type
ADAM18 p.Ala477Thr Uncertain significance ★ ⚠ same type
ADAM18 p.Ala6Thr Uncertain significance ★ ⚠ same type
ADAM18 p.Arg135Thr Uncertain significance ★ ⚠ same type
ADAM18 p.Arg255Ile 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/adam18-p-cys360phe (accessed [today's date]).

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