Is EBF4 p.Phe541Ser (c.1622T>C) pathogenic?

EBF4 p.Phe541Ser (c.1622T>C) is classified Uncertain significance in EBF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.9508); Very rare (popmax 0.00157%, nfe).

How common is EBF4 p.Phe541Ser (c.1622T>C) in the general population?

EBF4 p.Phe541Ser (c.1622T>C) is very rare (popmax 0.00157%, nfe) (gnomAD).

What do computational predictors say about EBF4 p.Phe541Ser (c.1622T>C)?

AlphaMissense predicts likely pathogenic (score 0.9508) — an in-silico prediction, not a clinical call.

EBF4 p.Phe541Ser

c.1622T>C · VCV3274353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9508 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00157%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9508	likely pathogenic
REVEL	0.163	moderately benign-leaning
SaProt	LLR -2.73	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.1	GERP 0.46, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 9,329 bp · p 0.2 · regional, not allelic
Overall
CADD	27.4	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 0.00157% European (non-Finnish) · 18/1,146,806 alleles

Filtering AF 0.000981% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000809%

Overall 0.00116% 18/1,550,688 alleles · very rare exomes 18/1,398,834 · genomes 0/151,854 · joint denominator

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: EBF4
Protein: p.Phe541Ser
Coding: c.1622T>C
MANE Select: NM_001395167
Type: single nucleotide variant
Location: chr20:2755708 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.60

Full EBF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EBF4 p.Arg164= Benign ★★ same type
EBF4 p.Ile91= Benign ★★ same type
EBF4 p.Ala102Thr Uncertain significance ★ ⚠ same type
EBF4 p.Ala102Val Uncertain significance ★ ⚠ same type
EBF4 p.Ala402Thr Uncertain significance ★ ⚠ same type
EBF4 p.Ala40Thr Uncertain significance ★ ⚠ same type
EBF4 p.Ala438Ser Uncertain significance ★ ⚠ same type
EBF4 p.Ala522Val 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/ebf4-p-phe541ser (accessed [today's date]).

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