Is EGF p.Leu1043Phe (c.3127C>T) pathogenic?

EGF p.Leu1043Phe (c.3127C>T) is classified Benign/Likely benign in EGF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.1175); Low-frequency (popmax 2.96%, afr).

How common is EGF p.Leu1043Phe (c.3127C>T) in the general population?

EGF p.Leu1043Phe (c.3127C>T) is low-frequency (popmax 2.96%, afr) (gnomAD).

What do computational predictors say about EGF p.Leu1043Phe (c.3127C>T)?

AlphaMissense predicts likely benign (score 0.1175) — an in-silico prediction, not a clinical call.

EGF p.Leu1043Phe

c.3127C>T · rs11569098 · VCV445644

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1175 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.96%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1175	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -7.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.00042 · regional, not allelic
Overall
CADD	18.19	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 2.96% African / African-American · 2,222/75,020 alleles

Filtering AF 2.86% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.82%

Overall 0.156% 2,518/1,613,918 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.96%	34
Remaining individualsnot grpmax-eligible	0.205%	488
Admixed American	0.19%	526
Middle Eastern	0.136%	735
South Asian	0.0121%	8,278
European (non-Finnish)	0.00297%	33,715

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: EGF
Protein: p.Leu1043Phe
Coding: c.3127C>T
MANE Select: NM_001963
dbSNP: rs11569098
Type: single nucleotide variant
Location: chr4:109999800 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB
Residue 1043: a UniProt-annotated variant site (in)

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

Similar variants

EGF c.2221+4C>T Uncertain significance ★★ same type
EGF c.2858-11G>T Uncertain significance ★★ same type
EGF c.-60C>T Uncertain significance ★★ same type
EGF p.Ala1025Ser Uncertain significance ★★ ⚠ same type
EGF p.Ala1037Val Uncertain significance ★★ ⚠ same type
EGF p.Ala45Val Uncertain significance ★★ ⚠ same type
EGF p.Ala862Thr Uncertain significance ★★ ⚠ same type
EGF p.Arg213Gln 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/egf-p-leu1043phe (accessed [today's date]).

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