Is ADAM18 p.Ser246Arg (c.738T>A) pathogenic?

ADAM18 p.Ser246Arg (c.738T>A) is classified Uncertain significance in ADAM18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1317); Ultra-rare (popmax 0.0125%, nfe).

How common is ADAM18 p.Ser246Arg (c.738T>A) in the general population?

ADAM18 p.Ser246Arg (c.738T>A) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about ADAM18 p.Ser246Arg (c.738T>A)?

AlphaMissense predicts likely benign (score 0.1317) — an in-silico prediction, not a clinical call.

ADAM18 p.Ser246Arg

c.738T>A · rs747201163 · VCV2371778

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1317 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1317	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -7.00	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 -12	GERP -3.9
Regional constraint	o/e 1.06	unconstrained · MANE · 145 kb · p 0.059 · regional, not allelic
Overall
CADD	0.083	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 0.0125% European (non-Finnish) · 147/1,179,316 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00961% 155/1,612,728 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	8,023
East Asian	0.0112%	8,957
Remaining individualsnot grpmax-eligible	0.0032%	31,204
African / African-American	0.00134%	74,848

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.Ser246Arg
Coding: c.738T>A
MANE Select: NM_014237
dbSNP: rs747201163
Type: single nucleotide variant
Location: chr8:39637614 (GRCh38)
Gene constraint: LOEUF 1.585 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.24
Residue 246: 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-ser246arg (accessed [today's date]).

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