Is EXT1 p.Ser720Cys (c.2159C>G) pathogenic?

EXT1 p.Ser720Cys (c.2159C>G) is classified Uncertain significance in EXT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-01-31). AlphaMissense: likely pathogenic (0.8959); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXT1 p.Ser720Cys (c.2159C>G)?

EXT1 p.Ser720Cys (c.2159C>G) is associated with Inborn genetic diseases, hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Ser720Cys (c.2159C>G) in the general population?

EXT1 p.Ser720Cys (c.2159C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about EXT1 p.Ser720Cys (c.2159C>G)?

AlphaMissense predicts likely pathogenic (score 0.8959) — an in-silico prediction, not a clinical call.

EXT1 p.Ser720Cys

c.2159C>G · rs1373349863 · VCV912088

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8959	likely pathogenic
REVEL	0.767	pathogenic-leaning
SaProt	LLR -12.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 13 kb · p 1.9e-10 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000424% European (non-Finnish) · 5/1,180,044 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,206 alleles · very rare exomes 5/1,461,890 · genomes 0/152,316 · joint denominator

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: EXT1
Protein: p.Ser720Cys
Coding: c.2159C>G
MANE Select: NM_000127
dbSNP: rs1373349863
Type: single nucleotide variant
Location: chr8:117799794 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB

Full EXT1 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: hereditary multiple osteochondromas

Similar variants

EXT1 p.Ser720Ala Uncertain significance ★ ⚠ same residue
EXT1 c.1056+1G>A Pathogenic ★★ same condition
EXT1 c.1056+1G>T Pathogenic ★★ same condition
EXT1 c.1165-1G>A Pathogenic ★★ same condition
EXT1 c.1285-1G>C Pathogenic ★★ same condition
EXT1 c.1417+1G>A Pathogenic ★★ same condition
EXT1 c.1417+1G>T Pathogenic ★★ same condition
EXT1 c.1418-1G>A 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/ext1-p-ser720cys (accessed [today's date]).

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