Is ADAM23 p.Ser735Arg (c.2203A>C) pathogenic?

ADAM23 p.Ser735Arg (c.2203A>C) is classified Uncertain significance in ADAM23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: ambiguous (0.5167); Ultra-rare (popmax 0.033%, mid).

How common is ADAM23 p.Ser735Arg (c.2203A>C) in the general population?

ADAM23 p.Ser735Arg (c.2203A>C) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about ADAM23 p.Ser735Arg (c.2203A>C)?

AlphaMissense predicts ambiguous (score 0.5167) — an in-silico prediction, not a clinical call.

ADAM23 p.Ser735Arg

c.2203A>C · VCV4226071

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5167 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5167	ambiguous
REVEL	0.131	moderately benign-leaning
SaProt	LLR -7.49	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 129 kb · p 5.6e-12 · regional, not allelic
Overall
CADD	26.5	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00899% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00248% 40/1,614,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Admixed American	0.0167%	6,002
Remaining individualsnot grpmax-eligible	0.0048%	20,835
South Asian	0.0022%	45,542
European (non-Finnish)	0.00195%	51,305

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: ADAM23
Protein: p.Ser735Arg
Coding: c.2203A>C
MANE Select: NM_003812
Type: single nucleotide variant
Location: chr2:206594861 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.38
Residue 735: the egf-like domain

Full ADAM23 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM23 p.Ile118Met Likely benign ★★ ⚠ same type
ADAM23 p.Phe158= Likely benign ★★ same type
ADAM23 p.Pro780Ala Benign/Likely benign ★★ same type
ADAM23 p.Ser125Ala Likely benign ★★ same type
ADAM23 p.Ser693= Benign ★★ same type
ADAM23 c.1346-1G>C Uncertain significance ★ same type
ADAM23 p.Ala145Gly Uncertain significance ★ ⚠ same type
ADAM23 p.Ala287Thr 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/adam23-p-ser735arg (accessed [today's date]).

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