Is DYSF p.Pro1417Ser (c.4249C>T) pathogenic?

DYSF p.Pro1417Ser (c.4249C>T) is classified Uncertain significance in DYSF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2017-05-26). AlphaMissense: likely pathogenic (0.5685); Very rare (popmax 0.00223%, eas).

How common is DYSF p.Pro1417Ser (c.4249C>T) in the general population?

DYSF p.Pro1417Ser (c.4249C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DYSF p.Pro1417Ser (c.4249C>T)?

AlphaMissense predicts likely pathogenic (score 0.5685) — an in-silico prediction, not a clinical call.

DYSF p.Pro1417Ser

c.4249C>T · rs376134165 · VCV432288

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5685	likely pathogenic
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -10.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 117 kb · p 0.28 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1399S vs ClinVar P1417S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
African / African-American	0.00133%	74,922
European (non-Finnish)	0.000508%	196,671

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.Pro1417Ser
Coding: c.4249C>T
MANE Select: NM_001130987
dbSNP: rs376134165
Type: single nucleotide variant
Location: chr2:71612668 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1417: a β-strand; the c2 5 domain

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

Similar variants

DYSF p.Pro1417Ala Uncertain significance ★ ⚠ same residue
DYSF p.Pro1417= Likely benign ★ same residue
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

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-pro1417ser (accessed [today's date]).

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