Is EGF p.Val554Leu (c.1660G>C) pathogenic?

EGF p.Val554Leu (c.1660G>C) is classified Uncertain significance in EGF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely benign (0.1627); Very rare (popmax 8.47e-05%, nfe).

How common is EGF p.Val554Leu (c.1660G>C) in the general population?

EGF p.Val554Leu (c.1660G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EGF p.Val554Leu (c.1660G>C)?

AlphaMissense predicts likely benign (score 0.1627) — an in-silico prediction, not a clinical call.

EGF p.Val554Leu

c.1660G>C · rs1747129339 · VCV2720957

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1627	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -3.93	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 -0.17	GERP -3.8
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.00042 · regional, not allelic
Overall
CADD	2.906	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.84e-05% 1/1,461,888 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.Val554Leu
Coding: c.1660G>C
MANE Select: NM_001963
dbSNP: rs1747129339
Type: single nucleotide variant
Location: chr4:109969055 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB

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-val554leu (accessed [today's date]).

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