Is E4F1 p.Ser205Cys (c.613A>T) pathogenic?

E4F1 p.Ser205Cys (c.613A>T) is classified Uncertain significance in E4F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-25). AlphaMissense: likely pathogenic (0.7036); Very rare (popmax 0.000339%, nfe).

How common is E4F1 p.Ser205Cys (c.613A>T) in the general population?

E4F1 p.Ser205Cys (c.613A>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about E4F1 p.Ser205Cys (c.613A>T)?

AlphaMissense predicts likely pathogenic (score 0.7036) — an in-silico prediction, not a clinical call.

E4F1 p.Ser205Cys

c.613A>T · VCV3506324

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7036	likely pathogenic
REVEL	0.538	indeterminate
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.59	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,165 bp · p 0.86 · regional, not allelic
Overall
CADD	27.1	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 0.000339% European (non-Finnish) · 4/1,179,094 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,458,434 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: E4F1
Protein: p.Ser205Cys
Coding: c.613A>T
MANE Select: NM_004424
Type: single nucleotide variant
Location: chr16:2232459 (GRCh38)
Gene constraint: LOEUF 0.638 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.68
Residue 205: the 'mediates dimerization, dna-binding, transcription repression of ccna2 and interaction with hmga2' region

Full E4F1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

E4F1 p.Arg490His Uncertain significance ★★ ⚠ same type
E4F1 p.Lys144Gln Likely pathogenic ★ ⚠ same type
E4F1 p.Ala124Val Uncertain significance ★ ⚠ same type
E4F1 p.Ala152Val Uncertain significance ★ ⚠ same type
E4F1 p.Ala15Thr Uncertain significance ★ ⚠ same type
E4F1 p.Ala21Asp Uncertain significance ★ ⚠ same type
E4F1 p.Ala21Ser Uncertain significance ★ ⚠ same type
E4F1 p.Ala292Thr 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/e4f1-p-ser205cys (accessed [today's date]).

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