Is ADAM20 p.Val237Phe (c.709G>T) pathogenic?

ADAM20 p.Val237Phe (c.709G>T) is classified Uncertain significance in ADAM20 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.5831); Very rare (popmax 8.48e-05%, nfe).

How common is ADAM20 p.Val237Phe (c.709G>T) in the general population?

ADAM20 p.Val237Phe (c.709G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ADAM20 p.Val237Phe (c.709G>T)?

AlphaMissense predicts likely pathogenic (score 0.5831) — an in-silico prediction, not a clinical call.

ADAM20 p.Val237Phe

c.709G>T · VCV4637360

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5831	likely pathogenic
REVEL	0.369	indeterminate
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -3.7
Regional constraint	o/e 0.99	unconstrained · MANE · 2,177 bp · p 0.68 · regional, not allelic
Overall
CADD	9.754	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 8.48e-05% European (non-Finnish) · 1/1,179,918 alleles

Overall 6.84e-05% 1/1,461,596 alleles · very rare

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: ADAM20
Protein: p.Val237Phe
Coding: c.709G>T
MANE Select: NM_003814
Type: single nucleotide variant
Location: chr14:70524049 (GRCh38)
Gene constraint: LOEUF 1.933 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 83.06
Residue 237: the peptidase m12b domain

Full ADAM20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM20 p.Val237Ile Uncertain significance ★ ⚠ same residue
ADAM20 c.-117A>T Uncertain significance ★ same type
ADAM20 c.-125A>G Uncertain significance ★ same type
ADAM20 c.-63G>A Uncertain significance ★ same type
ADAM20 c.-71C>G Uncertain significance ★ same type
ADAM20 c.-77G>A Uncertain significance ★ same type
ADAM20 c.-90A>G Uncertain significance ★ same type
ADAM20 p.Ala124Pro 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/adam20-p-val237phe (accessed [today's date]).

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