Is ADAMTSL4 p.Ser759Phe (c.2276C>T) pathogenic?

ADAMTSL4 p.Ser759Phe (c.2276C>T) is classified Uncertain significance in ADAMTSL4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-30). AlphaMissense: likely benign (0.2769); Ultra-rare (popmax 0.0307%, sas); Associated with ectopia lentis 2, isolated, autosomal recessive.

What condition is associated with ADAMTSL4 p.Ser759Phe (c.2276C>T)?

ADAMTSL4 p.Ser759Phe (c.2276C>T) is associated with ectopia lentis 2, isolated, autosomal recessive, ectopia lentis et pupillae (ClinVar).

How common is ADAMTSL4 p.Ser759Phe (c.2276C>T) in the general population?

ADAMTSL4 p.Ser759Phe (c.2276C>T) is ultra-rare (popmax 0.0307%, sas) (gnomAD).

What do computational predictors say about ADAMTSL4 p.Ser759Phe (c.2276C>T)?

AlphaMissense predicts likely benign (score 0.2769) — an in-silico prediction, not a clinical call.

ADAMTSL4 p.Ser759Phe

c.2276C>T · rs772998470 · VCV2145608

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2769 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ectopia lentis 2, isolated, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.2769	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -7.30	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 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,904 bp · p 0.23 · regional, not allelic
Overall
CADD	24.1	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 0.0307% South Asian · 28/91,082 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00291% 47/1,612,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0307%	3,253
Middle Eastern	0.0165%	6,076
Remaining individualsnot grpmax-eligible	0.0048%	20,820
Finnishnot grpmax-eligible	0.00318%	31,464
East Asian	0.00223%	44,884
European (non-Finnish)	0.00102%	98,326

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: ADAMTSL4
Protein: p.Ser759Phe
Coding: c.2276C>T
MANE Select: NM_019032
dbSNP: rs772998470
Type: single nucleotide variant
Location: chr1:150558043 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.18
Residue 759: the tsp type-1 2 domain

Full ADAMTSL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ectopia lentis 2, isolated, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ectopia lentis et pupillae

Similar variants

ADAMTSL4 p.Ser759= Likely benign ★ same residue
ADAMTSL4 c.2178-2A>G Likely pathogenic ★★ same condition
ADAMTSL4 p.Arg1007Ter Pathogenic/Likely pathogenic ★★ same condition
ADAMTSL4 p.Arg141Ter Pathogenic ★★ same condition
ADAMTSL4 p.Arg670Ter Pathogenic/Likely pathogenic ★★ same condition
ADAMTSL4 p.Arg746His Pathogenic ★★ same condition
ADAMTSL4 p.Arg865His Pathogenic/Likely pathogenic ★★ same condition
ADAMTSL4 p.Cys799Ter Pathogenic ★★ 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/adamtsl4-p-ser759phe (accessed [today's date]).

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