Is ADAMTSL1 p.Ser1663Pro (c.4987T>C) pathogenic?

ADAMTSL1 p.Ser1663Pro (c.4987T>C) is classified Uncertain significance in ADAMTSL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.4742); Ultra-rare (popmax 0.0556%, nfe).

How common is ADAMTSL1 p.Ser1663Pro (c.4987T>C) in the general population?

ADAMTSL1 p.Ser1663Pro (c.4987T>C) is ultra-rare (popmax 0.0556%, nfe) (gnomAD).

What do computational predictors say about ADAMTSL1 p.Ser1663Pro (c.4987T>C)?

AlphaMissense predicts ambiguous (score 0.4742) — an in-silico prediction, not a clinical call.

ADAMTSL1 p.Ser1663Pro

c.4987T>C · rs202142719 · VCV2588631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0556%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4742	ambiguous
REVEL	0.315	indeterminate
SaProt	LLR -11.51	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.89, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 434 kb · p 4.2e-17 · regional, not allelic
Overall
CADD	23.5	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 0.0556% European (non-Finnish) · 654/1,176,932 alleles

Filtering AF 0.052% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0506%

Overall 0.0423% 680/1,607,840 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0556%	1,800
Remaining individualsnot grpmax-eligible	0.0289%	3,457
Middle Eastern	0.0165%	6,072
Finnishnot grpmax-eligible	0.00471%	21,248
African / African-American	0.00401%	24,936
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,314

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: ADAMTSL1
Protein: p.Ser1663Pro
Coding: c.4987T>C
MANE Select: NM_001040272
dbSNP: rs202142719
Type: single nucleotide variant
Location: chr9:18906717 (GRCh38)
Gene constraint: LOEUF 0.744 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.26

Full ADAMTSL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAMTSL1 p.Tyr55Cys Uncertain significance ★★ ⚠ same type
ADAMTSL1 c.3678-8C>T Benign/Likely benign ★★ same type
ADAMTSL1 p.Arg1125His Likely benign ★★ same type
ADAMTSL1 p.Asn1004= Benign ★★ same type
ADAMTSL1 p.Asp1079= Benign ★★ same type
ADAMTSL1 p.Gln721= Benign ★★ same type
ADAMTSL1 p.Gly68= Benign ★★ same type
ADAMTSL1 p.Leu35= Benign ★★ 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/adamtsl1-p-ser1663pro (accessed [today's date]).

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