Is ACAN p.Val1380Phe (c.4138G>T) pathogenic?

ACAN p.Val1380Phe (c.4138G>T) is classified Pathogenic in ACAN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-02-18). AlphaMissense: ambiguous (0.4601); Absent from gnomAD v4.1; Associated with spondyloepimetaphyseal dysplasia, aggrecan type.

What condition is associated with ACAN p.Val1380Phe (c.4138G>T)?

ACAN p.Val1380Phe (c.4138G>T) is associated with spondyloepimetaphyseal dysplasia, aggrecan type (ClinVar).

How common is ACAN p.Val1380Phe (c.4138G>T) in the general population?

ACAN p.Val1380Phe (c.4138G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACAN p.Val1380Phe (c.4138G>T)?

AlphaMissense predicts ambiguous (score 0.4601) — an in-silico prediction, not a clinical call.

ACAN p.Val1380Phe

Q: How is Spondyloepimetaphyseal dysplasia, aggrecan type inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.4138G>T · rs1567185220 · VCV618999

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4601 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

spondyloepimetaphyseal dysplasia, aggrecan type

Computational evidence

Protein change
AlphaMissense	0.4601	ambiguous
REVEL	0.238	benign-leaning
SaProt	LLR -13.11	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -3.3, phastCons 0.01
Regional constraint	o/e 0.38	unconstrained · MANE · 1,434 bp · p 4e-11 · regional, not allelic
Overall
CADD	12.04	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACAN
Protein: p.Val1380Phe
Coding: c.4138G>T
MANE Select: NM_001369268
dbSNP: rs1567185220
Type: single nucleotide variant
Location: chr15:88856723 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 1380: the 'cs-1' region; the '35 x 19 aa approximate tandem repeats of e-[ivdg]-[lv]-[ev]-[gti]-[sta]-[atv]-[sp]-[ga]-[vifad]-[gedl]-[de]-[lvi]-[sg]-[gerk]-[lv]-p-s-g' region

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

Disease context

spondyloepimetaphyseal dysplasia, aggrecan type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spondyloepimetaphyseal dysplasia, aggrecan type (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACAN p.Arg675Ter Pathogenic/Likely pathogenic ★★ same condition
ACAN p.Asp2419Asn Likely pathogenic ★★ same condition
ACAN p.Tyr164Ter Pathogenic ★★ same condition
ACAN p.Ala171Val Uncertain significance ★★ ⚠ same condition
ACAN p.Arg2503Gln Uncertain significance ★★ ⚠ same condition
ACAN p.Arg2560Trp Uncertain significance ★★ ⚠ same condition
ACAN p.Arg279Gln Uncertain significance ★★ ⚠ same condition
ACAN p.Ile2315= 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/acan-p-val1380phe (accessed [today's date]).

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