Is DYSF p.Asp16His (c.46G>C) pathogenic?

DYSF p.Asp16His (c.46G>C) is classified Conflicting classifications of pathogenicity in DYSF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.7119); Very rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with DYSF p.Asp16His (c.46G>C)?

DYSF p.Asp16His (c.46G>C) is associated with Inborn genetic diseases, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

How common is DYSF p.Asp16His (c.46G>C) in the general population?

DYSF p.Asp16His (c.46G>C) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about DYSF p.Asp16His (c.46G>C)?

AlphaMissense predicts likely pathogenic (score 0.7119) — an in-silico prediction, not a clinical call.

DYSF p.Asp16His

c.46G>C · rs140603487 · VCV2058399

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7119	likely pathogenic
REVEL	0.495	indeterminate
SaProt	LLR -7.11	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 12	GERP 1.5, phastCons 1
Overall
CADD	25.8	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 0.01% Admixed American · 6/60,006 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00161% 26/1,614,030 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
African / African-American	0.004%	24,975
European (non-Finnish)	0.00144%	69,414

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.Asp16His
Coding: c.46G>C
MANE Select: NM_001130987 · reported on NM_003494
dbSNP: rs140603487
Type: single nucleotide variant
Location: chr2:71454044 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 16: a β-strand; the c2 1 domain

Full DYSF 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: neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Similar variants

DYSF c.1003-3C>A Pathogenic ★★★ same condition
DYSF c.1033+1G>A Pathogenic ★★★ same condition
DYSF c.1033+4A>T Likely pathogenic ★★★ same condition
DYSF c.1149+1G>A Pathogenic ★★★ same condition
DYSF c.1149+4A>G Pathogenic ★★★ same condition
DYSF c.1276+5G>A Pathogenic ★★★ same condition
DYSF c.1276+5G>C Pathogenic ★★★ same condition
DYSF c.1481-1G>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/dysf-p-asp16his (accessed [today's date]).

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