Is E2F4 p.Asp397Asn (c.1189G>A) pathogenic?

E2F4 p.Asp397Asn (c.1189G>A) is classified Uncertain significance in E2F4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely pathogenic (0.8552); Very rare (popmax 0.000254%, nfe).

How common is E2F4 p.Asp397Asn (c.1189G>A) in the general population?

E2F4 p.Asp397Asn (c.1189G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about E2F4 p.Asp397Asn (c.1189G>A)?

AlphaMissense predicts likely pathogenic (score 0.8552) — an in-silico prediction, not a clinical call.

E2F4 p.Asp397Asn

c.1189G>A · rs1437937934 · VCV2483983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8552 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8552	likely pathogenic
REVEL	0.479	indeterminate
SaProt	LLR -6.37	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,701 bp · p 0.93 · regional, not allelic
Overall
CADD	32.0	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 0.000254% European (non-Finnish) · 3/1,179,996 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,766 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	0.000254%	393,332

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: E2F4
Protein: p.Asp397Asn
Coding: c.1189G>A
MANE Select: NM_001950
dbSNP: rs1437937934
Type: single nucleotide variant
Location: chr16:67198070 (GRCh38)
Gene constraint: LOEUF 0.615 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 65.56 · 2 PDB
Residue 397: the 'transactivation' region; the 'interaction with rbl1 and rbl2' region

Full E2F4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E2F4 p.Ala138Val Uncertain significance ★ ⚠ same type
E2F4 p.Ala150Thr Uncertain significance ★ ⚠ same type
E2F4 p.Ala239Gly Uncertain significance ★ ⚠ same type
E2F4 p.Ala239Pro Uncertain significance ★ ⚠ same type
E2F4 p.Ala2Gly Uncertain significance ★ ⚠ same type
E2F4 p.Ala340Ser Uncertain significance ★ ⚠ same type
E2F4 p.Ala4Pro Uncertain significance ★ ⚠ same type
E2F4 p.Arg126Gln Uncertain significance ★ ⚠ 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/e2f4-p-asp397asn (accessed [today's date]).

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