Is ADAMTS4 p.Ser100Pro (c.298T>C) pathogenic?

ADAMTS4 p.Ser100Pro (c.298T>C) is classified Likely benign in ADAMTS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely benign (0.0477); Rare (popmax 0.156%, nfe).

How common is ADAMTS4 p.Ser100Pro (c.298T>C) in the general population?

ADAMTS4 p.Ser100Pro (c.298T>C) is rare (popmax 0.156%, nfe) (gnomAD).

What do computational predictors say about ADAMTS4 p.Ser100Pro (c.298T>C)?

AlphaMissense predicts likely benign (score 0.0477) — an in-silico prediction, not a clinical call.

ADAMTS4 p.Ser100Pro

c.298T>C · rs113202559 · VCV3024829

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0477 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.156%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0477	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -5.04	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 5.1	GERP -0.65, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,486 bp · p 0.0021 · regional, not allelic
Overall
CADD	15.71	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 0.156% European (non-Finnish) · 1,835/1,179,998 alleles

Filtering AF 0.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.126% 2,030/1,613,344 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.49%	18
European (non-Finnish)grpmax	0.156%	643
Remaining individualsnot grpmax-eligible	0.109%	919
Admixed American	0.0716%	1,396
Middle Eastern	0.0495%	2,021
African / African-American	0.0213%	4,691
Finnishnot grpmax-eligible	0.0142%	7,028
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
South Asian	0.00329%	30,359

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser100Pro
Coding: c.298T>C
MANE Select: NM_005099
dbSNP: rs113202559
Type: single nucleotide variant
Location: chr1:161198330 (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-ser100pro (accessed [today's date]).

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