Is EXTL3 p.Pro583Ser (c.1747C>T) pathogenic?

EXTL3 p.Pro583Ser (c.1747C>T) is classified Uncertain significance in EXTL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-15). AlphaMissense: likely benign (0.1893); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with EXTL3 p.Pro583Ser (c.1747C>T)?

EXTL3 p.Pro583Ser (c.1747C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXTL3 p.Pro583Ser (c.1747C>T) in the general population?

EXTL3 p.Pro583Ser (c.1747C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about EXTL3 p.Pro583Ser (c.1747C>T)?

AlphaMissense predicts likely benign (score 0.1893) — an in-silico prediction, not a clinical call.

EXTL3 p.Pro583Ser

c.1747C>T · rs1293620933 · VCV1904695

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1893	likely benign
REVEL	0.6	indeterminate
SaProt	LLR -6.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,803 bp · p 0.01 · regional, not allelic
Overall
CADD	23.9	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 0.00534% African / African-American · 4/74,894 alleles

Filtering AF 0.00216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00242% 39/1,612,524 alleles · very rare exomes 30/1,460,312 · genomes 9/152,212 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,724
European (non-Finnish)	0.00297%	33,680

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.Pro583Ser
Coding: c.1747C>T
MANE Select: NM_001440
dbSNP: rs1293620933
Type: single nucleotide variant
Location: chr8:28717806 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 84.22 · 4 PDB

Full EXTL3 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

EXTL3 p.Ala373Thr Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala385Val Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala481Val Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala482Thr Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala560Ser Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala585Thr Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala820Thr Uncertain significance ★★ same condition
EXTL3 p.Arg175Trp 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/extl3-p-pro583ser (accessed [today's date]).

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