Is ADAMTSL4 p.Arg751Trp (c.2251C>T) pathogenic?

ADAMTSL4 p.Arg751Trp (c.2251C>T) is classified Uncertain significance in ADAMTSL4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.1936); Ultra-rare (popmax 0.0223%, eas); Associated with Inborn genetic diseases.

What condition is associated with ADAMTSL4 p.Arg751Trp (c.2251C>T)?

ADAMTSL4 p.Arg751Trp (c.2251C>T) is associated with Inborn genetic diseases, ectopia lentis 2, isolated, autosomal recessive, ectopia lentis et pupillae (ClinVar).

How common is ADAMTSL4 p.Arg751Trp (c.2251C>T) in the general population?

ADAMTSL4 p.Arg751Trp (c.2251C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about ADAMTSL4 p.Arg751Trp (c.2251C>T)?

AlphaMissense predicts likely benign (score 0.1936) — an in-silico prediction, not a clinical call.

ADAMTSL4 p.Arg751Trp

c.2251C>T · rs371399521 · VCV875327

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1936 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1936	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -9.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	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 0.0223% East Asian · 10/44,866 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.008% 129/1,612,658 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,487
Middle Eastern	0.0166%	6,030
African / African-American	0.012%	8,339
Admixed American	0.0117%	8,574
Remaining individualsnot grpmax-eligible	0.008%	12,494
European (non-Finnish)	0.0078%	12,824
South Asian	0.00549%	18,212

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.Arg751Trp
Coding: c.2251C>T
MANE Select: NM_019032
dbSNP: rs371399521
Type: single nucleotide variant
Location: chr1:150558018 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.18
Residue 751: the tsp type-1 2 domain

Full ADAMTSL4 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

Also linked: ectopia lentis 2, isolated, autosomal recessive ectopia lentis et pupillae

Similar variants

ADAMTSL4 p.Arg751Gln Uncertain significance ★★ ⚠ same residue
ADAMTSL4 p.Arg751= 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

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-arg751trp (accessed [today's date]).

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