Is ADAM8 p.Pro692His (c.2075C>A) pathogenic?

ADAM8 p.Pro692His (c.2075C>A) is classified Uncertain significance in ADAM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-14). AlphaMissense: likely benign (0.1321); Very rare (popmax 0.00916%, afr).

How common is ADAM8 p.Pro692His (c.2075C>A) in the general population?

ADAM8 p.Pro692His (c.2075C>A) is very rare (popmax 0.00916%, afr) (gnomAD).

What do computational predictors say about ADAM8 p.Pro692His (c.2075C>A)?

AlphaMissense predicts likely benign (score 0.1321) — an in-silico prediction, not a clinical call.

ADAM8 p.Pro692His

c.2075C>A · rs866868319 · VCV3146108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1321 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00916%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.1321	likely benign
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 14 kb · p 0.43 · regional, not allelic
Overall
CADD	23.3	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 0.00916% African / African-American · 6/65,488 alleles

Filtering AF 0.00398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00266%

Overall 0.000551% 7/1,271,464 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00916%	10,915
Admixed American	0.00369%	27,112

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: ADAM8
Protein: p.Pro692His
Coding: c.2075C>A
MANE Select: NM_001109
dbSNP: rs866868319
Type: single nucleotide variant
Location: chr10:133268107 (GRCh38)
Gene constraint: LOEUF 1.423 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.28 · 1 PDB

Full ADAM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM8 p.Ala118= Benign ★★ same type
ADAM8 p.Ala490Thr Benign ★★ same type
ADAM8 p.Arg36His Benign ★★ ⚠ same type
ADAM8 p.Arg433Cys Benign ★★ ⚠ same type
ADAM8 c.228-2A>G Uncertain significance ★ same type
ADAM8 p.Ala119Ser Uncertain significance ★ ⚠ same type
ADAM8 p.Ala119Thr Uncertain significance ★ ⚠ same type
ADAM8 p.Ala164Ser 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/adam8-p-pro692his (accessed [today's date]).

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