Is EXTL3 p.Arg8Trp (c.22C>T) pathogenic?

EXTL3 p.Arg8Trp (c.22C>T) is classified Uncertain significance in EXTL3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-09-19). AlphaMissense: likely benign (0.1752); Ultra-rare (popmax 0.0167%, mid); Associated with immunoskeletal dysplasia with neurodevelopmental abnormalities.

What condition is associated with EXTL3 p.Arg8Trp (c.22C>T)?

EXTL3 p.Arg8Trp (c.22C>T) is associated with immunoskeletal dysplasia with neurodevelopmental abnormalities (ClinVar).

How common is EXTL3 p.Arg8Trp (c.22C>T) in the general population?

EXTL3 p.Arg8Trp (c.22C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about EXTL3 p.Arg8Trp (c.22C>T)?

AlphaMissense predicts likely benign (score 0.1752) — an in-silico prediction, not a clinical call.

EXTL3 p.Arg8Trp

c.22C>T · rs780815544 · VCV1033843

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1752 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunoskeletal dysplasia with neurodevelopmental abnormalities

Computational evidence

Protein change
AlphaMissense	0.1752	likely benign
REVEL	0.741	pathogenic-leaning
SaProt	LLR -9.45	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,803 bp · p 0.01 · regional, not allelic
Overall
CADD	32.0	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 0.0167% Middle Eastern · 1/5,990 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00584% 94/1,609,358 alleles · ultra-rare exomes 87/1,457,176 · genomes 7/152,182 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,990
Admixed American	0.0167%	6,000
Remaining individualsnot grpmax-eligible	0.00641%	15,609
European (non-Finnish)	0.0061%	16,387
African / African-American	0.00534%	18,732
South Asian	0.00329%	30,350

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: EXTL3
Protein: p.Arg8Trp
Coding: c.22C>T
MANE Select: NM_001440
dbSNP: rs780815544
Type: single nucleotide variant
Location: chr8:28716081 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 84.22 · 4 PDB
Residue 8: the 'required for interaction with reg3a' region

Full EXTL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunoskeletal dysplasia with neurodevelopmental abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EXTL3 p.Arg8Gln Uncertain significance ★ ⚠ same residue
EXTL3 p.Pro318Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
EXTL3 p.Ala507Ser Uncertain significance ★★ ⚠ same condition
EXTL3 p.Asn657Ser Uncertain significance ★★ ⚠ same condition
EXTL3 p.Glu736Gly Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ile829Thr Uncertain significance ★★ ⚠ same condition
EXTL3 p.Val442Leu Benign/Likely benign ★★ same condition
EXTL3 p.Arg158Ter 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/extl3-p-arg8trp (accessed [today's date]).

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