Is DAG1 p.Pro616Ser (c.1846C>T) pathogenic?

DAG1 p.Pro616Ser (c.1846C>T) is classified Uncertain significance in DAG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-21). AlphaMissense: likely benign (0.1915); Very rare (popmax 0.00801%, afr); Associated with Inborn genetic diseases.

How common is DAG1 p.Pro616Ser (c.1846C>T) in the general population?

DAG1 p.Pro616Ser (c.1846C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about DAG1 p.Pro616Ser (c.1846C>T)?

AlphaMissense predicts likely benign (score 0.1915) — an in-silico prediction, not a clinical call.

DAG1 p.Pro616Ser

Q: What condition is associated with DAG1 p.Pro616Ser (c.1846C>T)?

DAG1 p.Pro616Ser (c.1846C>T) is associated with Inborn genetic diseases, autosomal recessive limb-girdle muscular dystrophy type 2P, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9 (ClinVar).

c.1846C>T · rs372730352 · VCV1461758

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1915	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -3.55	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 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,883 bp · p 0.0007 · regional, not allelic
Overall
CADD	17.61	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 0.00801% African / African-American · 6/74,940 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000372% 6/1,614,018 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: DAG1
Protein: p.Pro616Ser
Coding: c.1846C>T
MANE Select: NM_004393
dbSNP: rs372730352
Type: single nucleotide variant
Location: chr3:49532357 (GRCh38)
Gene constraint: LOEUF 0.298 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.44 · 8 PDB
Residue 616: the peptidase s72 domain

Full DAG1 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: autosomal recessive limb-girdle muscular dystrophy type 2P muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9

Similar variants

DAG1 p.Pro616= Conflicting classifications of pathogenicity ★ same residue
DAG1 p.Pro616Leu Uncertain significance ★ ⚠ same residue
DAG1 p.Ser14Ter Pathogenic ★★ same condition
DAG1 p.Trp110Ter Pathogenic/Likely pathogenic ★★ same condition
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

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-pro616ser (accessed [today's date]).

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