Is EGF p.Leu369Pro (c.1106T>C) pathogenic?

EGF p.Leu369Pro (c.1106T>C) is classified Uncertain significance in EGF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-29). AlphaMissense: likely pathogenic (0.711); Very rare (popmax 8.48e-05%, nfe).

How common is EGF p.Leu369Pro (c.1106T>C) in the general population?

EGF p.Leu369Pro (c.1106T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about EGF p.Leu369Pro (c.1106T>C)?

AlphaMissense predicts likely pathogenic (score 0.711) — an in-silico prediction, not a clinical call.

EGF p.Leu369Pro

c.1106T>C · rs765529399 · VCV2262474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.711 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.711	likely pathogenic · top 10% in EGF
REVEL	0.684	pathogenic-leaning
SaProt	LLR -8.24	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.00042 · regional, not allelic
Overall
CADD	24.1	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 8.48e-05% European (non-Finnish) · 1/1,179,888 alleles

Overall 6.84e-05% 1/1,461,684 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: EGF
Protein: p.Leu369Pro
Coding: c.1106T>C
MANE Select: NM_001963
dbSNP: rs765529399
Type: single nucleotide variant
Location: chr4:109960906 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB
Residue 369: the egf-like 2; calcium-binding domain; a disulfide bond

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-leu369pro (accessed [today's date]).

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