Is ADAM2 p.Phe689Ser (c.2066T>C) pathogenic?

ADAM2 p.Phe689Ser (c.2066T>C) is classified Uncertain significance in ADAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.2433); Absent from gnomAD v4.1.

How common is ADAM2 p.Phe689Ser (c.2066T>C) in the general population?

ADAM2 p.Phe689Ser (c.2066T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAM2 p.Phe689Ser (c.2066T>C)?

AlphaMissense predicts likely benign (score 0.2433) — an in-silico prediction, not a clinical call.

ADAM2 p.Phe689Ser

c.2066T>C · rs2536558948 · VCV3144649

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2433 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2433	likely benign
REVEL	0.431	indeterminate
SaProt	LLR -7.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.8, phastCons 0.78
Regional constraint	o/e 1.08	unconstrained · MANE · 93 kb · p 0.019 · regional, not allelic
Overall
CADD	18.69	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADAM2
Protein: p.Phe689Ser
Coding: c.2066T>C
MANE Select: NM_001464
dbSNP: rs2536558948
Type: single nucleotide variant
Location: chr8:39746580 (GRCh38)
Gene constraint: LOEUF 1.188 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.05

Full ADAM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM2 p.Ala238Val Uncertain significance ★ ⚠ same type
ADAM2 p.Ala266Gly Uncertain significance ★ ⚠ same type
ADAM2 p.Ala289Val Uncertain significance ★ ⚠ same type
ADAM2 p.Ala334Thr Uncertain significance ★ ⚠ same type
ADAM2 p.Ala463Val Uncertain significance ★ ⚠ same type
ADAM2 p.Ala668Val Uncertain significance ★ ⚠ same type
ADAM2 p.Arg161Gly Uncertain significance ★ ⚠ same type
ADAM2 p.Arg252Gly 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/adam2-p-phe689ser (accessed [today's date]).

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