Is DAG1 p.Ser180Phe (c.539C>T) pathogenic?

DAG1 p.Ser180Phe (c.539C>T) is classified Uncertain significance in DAG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-06). AlphaMissense: likely benign (0.0728); Ultra-rare (popmax 0.0183%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2P.

What condition is associated with DAG1 p.Ser180Phe (c.539C>T)?

DAG1 p.Ser180Phe (c.539C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2P, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9 (ClinVar).

How common is DAG1 p.Ser180Phe (c.539C>T) in the general population?

DAG1 p.Ser180Phe (c.539C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about DAG1 p.Ser180Phe (c.539C>T)?

AlphaMissense predicts likely benign (score 0.0728) — an in-silico prediction, not a clinical call.

DAG1 p.Ser180Phe

Q: How is Alpha-dystroglycan-related limb-girdle muscular dystrophy R16 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.539C>T · rs756584618 · VCV497556

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0728 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2P

Computational evidence

Protein change
AlphaMissense	0.0728	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP 2, phastCons 0.057
Regional constraint	o/e 0.82	unconstrained · MANE · 21 kb · p 0.0053 · regional, not allelic
Overall
CADD	16.56	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,022 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000889% 13/1,461,894 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,457
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	8.47e-05%	1,180,045

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: DAG1
Protein: p.Ser180Phe
Coding: c.539C>T
MANE Select: NM_004393
dbSNP: rs756584618
Type: single nucleotide variant
Location: chr3:49531050 (GRCh38)
Gene constraint: LOEUF 0.298 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.44 · 8 PDB
Residue 180: the 'required for laminin recognition' region; the 'o-glycosylated at one site' region

Full DAG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2P — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9

For Alpha-dystroglycan-related limb-girdle muscular dystrophy R16 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

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DAG1 p.Ala135Ser Uncertain significance ★★ ⚠ same condition
DAG1 p.Ala135Thr Uncertain significance ★★ ⚠ same condition
DAG1 p.Ala279Ser Uncertain significance ★★ ⚠ same condition
DAG1 p.Ala285Thr Uncertain significance ★★ ⚠ same condition
DAG1 p.Ala285Val Uncertain significance ★★ ⚠ same condition
DAG1 p.Ala610Val 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/dag1-p-ser180phe (accessed [today's date]).

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