Is ADAM23 p.Phe625Ser (c.1874T>C) pathogenic?

ADAM23 p.Phe625Ser (c.1874T>C) is classified Uncertain significance in ADAM23 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely pathogenic (0.7254); Very rare (popmax 0.00834%, amr).

How common is ADAM23 p.Phe625Ser (c.1874T>C) in the general population?

ADAM23 p.Phe625Ser (c.1874T>C) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about ADAM23 p.Phe625Ser (c.1874T>C)?

AlphaMissense predicts likely pathogenic (score 0.7254) — an in-silico prediction, not a clinical call.

ADAM23 p.Phe625Ser

c.1874T>C · rs552972249 · VCV3145139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7254 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7254	likely pathogenic
REVEL	0.232	benign-leaning
SaProt	LLR -10.70	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 129 kb · p 5.6e-12 · regional, not allelic
Overall
CADD	28.0	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 0.00834% Admixed American · 5/59,932 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00446% 72/1,613,636 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,986
European (non-Finnish)	0.00559%	17,877
Remaining individualsnot grpmax-eligible	0.0016%	62,466

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.Phe625Ser
Coding: c.1874T>C
MANE Select: NM_003812
dbSNP: rs552972249
Type: single nucleotide variant
Location: chr2:206589430 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.38

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-phe625ser (accessed [today's date]).

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