Is ACAN p.Val478Phe (c.1432G>T) pathogenic?

ACAN p.Val478Phe (c.1432G>T) is classified Uncertain significance in ACAN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-09). AlphaMissense: ambiguous (0.5249); Ultra-rare (popmax 0.0652%, mid); Associated with Inborn genetic diseases.

What condition is associated with ACAN p.Val478Phe (c.1432G>T)?

ACAN p.Val478Phe (c.1432G>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACAN p.Val478Phe (c.1432G>T) in the general population?

ACAN p.Val478Phe (c.1432G>T) is ultra-rare (popmax 0.0652%, mid) (gnomAD).

What do computational predictors say about ACAN p.Val478Phe (c.1432G>T)?

AlphaMissense predicts ambiguous (score 0.5249) — an in-silico prediction, not a clinical call.

ACAN p.Val478Phe

c.1432G>T · rs748987964 · VCV1176637

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5249 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0652%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5249	ambiguous
REVEL	0.484	indeterminate
SaProt	LLR -8.69	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.86, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 19 kb · p 0.97 · regional, not allelic
Overall
CADD	23.4	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 0.0652% Middle Eastern · 3/4,600 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00943%

Overall 0.00168% 26/1,546,248 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0652%	1,533
Remaining individualsnot grpmax-eligible	0.0067%	14,926
Admixed American	0.0039%	25,635
African / African-American	0.00137%	73,112
European (non-Finnish)	0.00131%	76,261
South Asian	0.00119%	83,828

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: ACAN
Protein: p.Val478Phe
Coding: c.1432G>T
MANE Select: NM_001369268
dbSNP: rs748987964
Type: single nucleotide variant
Location: chr15:88847245 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.32 · 4 PDB
Residue 478: the link 3 domain; the 'g2-b' region

Full ACAN 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

ACAN p.Val478Ala Uncertain significance ★ ⚠ same residue
ACAN p.Leu1606Ter Pathogenic/Likely pathogenic ★★ same condition
ACAN p.Ala1404Ser Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2105Thr Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2163Thr Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2191Ser Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2278Asp Uncertain significance ★★ ⚠ same condition
ACAN p.Ala2409Gly 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-val478phe (accessed [today's date]).

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