Is DIP2A p.Ser1249Cys (c.3746C>G) pathogenic?

DIP2A p.Ser1249Cys (c.3746C>G) is classified Uncertain significance in DIP2A (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-15). AlphaMissense: likely benign (0.3035); Very rare (popmax 8.48e-05%, nfe); Associated with DIP2A-related disorder.

What condition is associated with DIP2A p.Ser1249Cys (c.3746C>G)?

DIP2A p.Ser1249Cys (c.3746C>G) is associated with DIP2A-related disorder (ClinVar).

How common is DIP2A p.Ser1249Cys (c.3746C>G) in the general population?

DIP2A p.Ser1249Cys (c.3746C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DIP2A p.Ser1249Cys (c.3746C>G)?

AlphaMissense predicts likely benign (score 0.3035) — an in-silico prediction, not a clinical call.

DIP2A p.Ser1249Cys

c.3746C>G · VCV3349850

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DIP2A-related disorder

Computational evidence

Protein change
AlphaMissense	0.3035	likely benign
REVEL	0.378	indeterminate
SaProt	LLR -10.86	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 108 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	28.1	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 8.48e-05% European (non-Finnish) · 1/1,179,788 alleles

Overall 6.84e-05% 1/1,461,310 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: DIP2A
Protein: p.Ser1249Cys
Coding: c.3746C>G
MANE Select: NM_015151
Type: single nucleotide variant
Location: chr21:46557701 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.93

Full DIP2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DIP2A-related disorder

Similar variants

DIP2A p.Ala1026Ser Uncertain significance ★ ⚠ same condition
DIP2A c.2637+25G>T Uncertain significance same condition
DIP2A p.Ala1260Ser Uncertain significance ⚠ same condition
DIP2A p.Arg602Trp Uncertain significance ⚠ same condition
DIP2A p.Glu63Asp Uncertain significance ⚠ same condition
DIP2A p.Lys281Thr Uncertain significance ⚠ same condition
DIP2A c.1707+7G>A Likely benign same condition
DIP2A c.1708-5C>G Benign 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/dip2a-p-ser1249cys (accessed [today's date]).

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