Is DIP2A p.Val1243Phe (c.3727G>T) pathogenic?

DIP2A p.Val1243Phe (c.3727G>T) is classified Uncertain significance in DIP2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: likely pathogenic (0.5995); Very rare (popmax 8.48e-05%, nfe).

How common is DIP2A p.Val1243Phe (c.3727G>T) in the general population?

DIP2A p.Val1243Phe (c.3727G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DIP2A p.Val1243Phe (c.3727G>T)?

AlphaMissense predicts likely pathogenic (score 0.5995) — an in-silico prediction, not a clinical call.

DIP2A p.Val1243Phe

c.3727G>T · VCV4011745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5995 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5995	likely pathogenic
REVEL	0.319	indeterminate
SaProt	LLR -7.50	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 6.5	GERP 0.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 108 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	25.7	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) · 1/1,179,848 alleles

Overall 0.000137% 2/1,461,316 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)grpmax	8.48e-05%	1,179,848

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val1243Phe
Coding: c.3727G>T
MANE Select: NM_015151
Type: single nucleotide variant
Location: chr21:46557682 (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

Similar variants

DIP2A p.Val1243Ile Uncertain significance ★ ⚠ same residue
DIP2A p.Ala676Thr Uncertain significance ★★ ⚠ same type
DIP2A p.Glu832Lys Uncertain significance ★★ ⚠ same type
DIP2A p.Pro333= Benign ★★ same type
DIP2A p.Pro798Leu Benign/Likely benign ★★ ⚠ same type
DIP2A p.Thr848= Benign/Likely benign ★★ same type
DIP2A p.Val1531= Benign ★★ same type
DIP2A c.1429+2T>G Likely 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/dip2a-p-val1243phe (accessed [today's date]).

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