Is VCAN p.Phe328Ser (c.983T>C) pathogenic?

VCAN p.Phe328Ser (c.983T>C) is classified Conflicting classifications of pathogenicity in VCAN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-11). AlphaMissense: likely pathogenic (0.9409); Ultra-rare (popmax 0.0573%, afr).

How common is VCAN p.Phe328Ser (c.983T>C) in the general population?

VCAN p.Phe328Ser (c.983T>C) is ultra-rare (popmax 0.0573%, afr) (gnomAD).

What do computational predictors say about VCAN p.Phe328Ser (c.983T>C)?

AlphaMissense predicts likely pathogenic (score 0.9409) — an in-silico prediction, not a clinical call.

VCAN p.Phe328Ser

c.983T>C · rs183969050 · VCV1055641

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9409 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0573%, afr)

Computational evidence

Protein change
AlphaMissense	0.9409	likely pathogenic · top 5% in VCAN
REVEL	0.569	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP -1.6, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 29 kb · p 6.4e-09 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0573% African / African-American · 43/74,984 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.039%

Overall 0.00385% 62/1,610,924 alleles · ultra-rare exomes 44/1,458,616 · genomes 18/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0573%	1,744
Middle Eastern	0.0165%	6,046
Remaining individualsnot grpmax-eligible	0.0144%	6,930
Admixed American	0.00834%	11,994
South Asian	0.0033%	30,332
European (non-Finnish)	8.49e-05%	1,177,309

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: VCAN
Protein: p.Phe328Ser
Coding: c.983T>C
MANE Select: NM_004385
dbSNP: rs183969050
Type: single nucleotide variant
Location: chr5:83512337 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Residue 328: the link 2 domain

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

Similar variants

VCAN p.Phe328Val Uncertain significance ★★ ⚠ same residue
VCAN c.4004-1G>A Pathogenic ★★ same type
VCAN c.4004-2A>C Pathogenic ★★ same type
VCAN c.4004-2A>G Pathogenic ★★ same type
VCAN c.4004-5T>C Pathogenic ★★ same type
VCAN c.9265+1G>C Pathogenic ★★ same type
VCAN c.9266-5G>A Uncertain significance ★★ same type
VCAN c.9493+5G>A Uncertain significance ★★ same type

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/vcan-p-phe328ser (accessed [today's date]).

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