Is ADAMTS18 p.Pro976Ser (c.2926C>T) pathogenic?

ADAMTS18 p.Pro976Ser (c.2926C>T) is classified Uncertain significance in ADAMTS18 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-15). AlphaMissense: ambiguous (0.4084); Very rare (popmax 0.00127%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ADAMTS18 p.Pro976Ser (c.2926C>T)?

ADAMTS18 p.Pro976Ser (c.2926C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ADAMTS18 p.Pro976Ser (c.2926C>T) in the general population?

ADAMTS18 p.Pro976Ser (c.2926C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about ADAMTS18 p.Pro976Ser (c.2926C>T)?

AlphaMissense predicts ambiguous (score 0.4084) — an in-silico prediction, not a clinical call.

ADAMTS18 p.Pro976Ser

c.2926C>T · rs763344799 · VCV1407120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4084	ambiguous
REVEL	0.25	benign-leaning
SaProt	LLR -9.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 151 kb · p 3.5e-38 · regional, not allelic
Overall
CADD	24.6	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 0.00127% European (non-Finnish) · 15/1,180,036 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,614,042 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: ADAMTS18
Protein: p.Pro976Ser
Coding: c.2926C>T
MANE Select: NM_199355
dbSNP: rs763344799
Type: single nucleotide variant
Location: chr16:77295003 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.83
Residue 976: the tsp type-1 2 domain

Full ADAMTS18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADAMTS18 p.Pro976= Likely benign ★ same residue
ADAMTS18 p.Ala186Val Uncertain significance ★★ ⚠ same condition
ADAMTS18 p.Ala207Thr Uncertain significance ★★ ⚠ same condition
ADAMTS18 p.Ala286Ser Uncertain significance ★★ ⚠ same condition
ADAMTS18 p.Ala527Thr Uncertain significance ★★ ⚠ same condition
ADAMTS18 p.Ala54Val Uncertain significance ★★ ⚠ same condition
ADAMTS18 p.Ala772Pro Uncertain significance ★★ ⚠ same condition
ADAMTS18 p.Ala870Asp Uncertain significance ★★ ⚠ same condition

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/adamts18-p-pro976ser (accessed [today's date]).

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