Is ADAM23 p.Pro34Ser (c.100C>T) pathogenic?

ADAM23 p.Pro34Ser (c.100C>T) is classified Uncertain significance in ADAM23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-17). AlphaMissense: likely benign (0.0803); Ultra-rare (popmax 0.012%, amr).

How common is ADAM23 p.Pro34Ser (c.100C>T) in the general population?

ADAM23 p.Pro34Ser (c.100C>T) is ultra-rare (popmax 0.012%, amr) (gnomAD).

What do computational predictors say about ADAM23 p.Pro34Ser (c.100C>T)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

ADAM23 p.Pro34Ser

c.100C>T · VCV4831443

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.96	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 2.8	GERP 0.77, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 37 kb · p 0.14 · regional, not allelic
Overall
CADD	18.35	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 0.012% Admixed American · 4/33,380 alleles

Filtering AF 0.00409% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00238%

Overall 0.000972% 13/1,337,400 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.012%	8,345
African / African-American	0.00607%	16,485
Remaining individualsnot grpmax-eligible	0.00202%	49,626
European (non-Finnish)	0.000384%	260,676

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.Pro34Ser
Coding: c.100C>T
MANE Select: NM_003812
Type: single nucleotide variant
Location: chr2:206443966 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.38
Residue 34: the 'disordered' region

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-pro34ser (accessed [today's date]).

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