Is ADAMTS4 p.Pro176Arg (c.527C>G) pathogenic?

ADAMTS4 p.Pro176Arg (c.527C>G) is classified Uncertain significance in ADAMTS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.121); Ultra-rare (popmax 0.01%, amr).

How common is ADAMTS4 p.Pro176Arg (c.527C>G) in the general population?

ADAMTS4 p.Pro176Arg (c.527C>G) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ADAMTS4 p.Pro176Arg (c.527C>G)?

AlphaMissense predicts likely benign (score 0.121) — an in-silico prediction, not a clinical call.

ADAMTS4 p.Pro176Arg

c.527C>G · rs1476816956 · VCV2598261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.121 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.121	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -6.67	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 8.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,486 bp · p 0.0021 · regional, not allelic
Overall
CADD	21.2	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 0.01% Admixed American · 6/59,946 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000434% 7/1,613,468 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,991
Remaining individualsnot grpmax-eligible	0.0016%	62,456

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: ADAMTS4
Protein: p.Pro176Arg
Coding: c.527C>G
MANE Select: NM_005099
dbSNP: rs1476816956
Type: single nucleotide variant
Location: chr1:161198101 (GRCh38)
Gene constraint: LOEUF 0.732 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.80 · 5 PDB

Full ADAMTS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAMTS4 c.*56A>G Benign ★★ same type
ADAMTS4 p.Ala115Val Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala20Ser Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala236Val Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala252Asp Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala286Val Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala313Gly Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala430Thr 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/adamts4-p-pro176arg (accessed [today's date]).

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