Is DYSF p.Val448Ala (c.1343T>C) pathogenic?

DYSF p.Val448Ala (c.1343T>C) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-13). AlphaMissense: likely pathogenic (0.7598); Very rare (popmax 0.00133%, afr).

How common is DYSF p.Val448Ala (c.1343T>C) in the general population?

DYSF p.Val448Ala (c.1343T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about DYSF p.Val448Ala (c.1343T>C)?

AlphaMissense predicts likely pathogenic (score 0.7598) — an in-silico prediction, not a clinical call.

DYSF p.Val448Ala

c.1343T>C · rs942200789 · VCV2441118

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7598	likely pathogenic
REVEL	0.559	indeterminate
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 85 kb · p 0.54 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V416A vs ClinVar V448A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,068 alleles

Overall 6.84e-05% 1/1,461,848 alleles · very rare

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: DYSF
Protein: p.Val448Ala
Coding: c.1343T>C
MANE Select: NM_001130987
dbSNP: rs942200789
Type: single nucleotide variant
Location: chr2:71528364 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 448: a β-strand; the c2 3 domain

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

Similar variants

DYSF c.1003-3C>A Pathogenic ★★★ same type
DYSF c.1033+1G>A Pathogenic ★★★ same type
DYSF c.1033+4A>T Likely pathogenic ★★★ same type
DYSF c.1033+5G>A Likely pathogenic ★★★ same type
DYSF c.1149+1G>A Pathogenic ★★★ same type
DYSF c.1149+1G>C Pathogenic ★★★ same type
DYSF c.1149+4A>G Pathogenic ★★★ same type
DYSF c.1149+5G>A Pathogenic ★★★ 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/dysf-p-val448ala (accessed [today's date]).

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