Is EGF p.Arg546= (c.1636C>A) pathogenic?

EGF p.Arg546= (c.1636C>A) is classified Likely benign in EGF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). Ultra-rare (popmax 0.012%, afr).

How common is EGF p.Arg546= (c.1636C>A) in the general population?

EGF p.Arg546= (c.1636C>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

EGF p.Arg546=

c.1636C>A · rs756376698 · VCV2142109

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -3.8
Overall
CADD	5.697	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,888 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00062% 10/1,613,966 alleles · ultra-rare exomes 5/1,461,874 · genomes 5/152,092 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,321
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg546=
Coding: c.1636C>A
MANE Select: NM_001963
dbSNP: rs756376698
Type: single nucleotide variant
Location: chr4:109969031 (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 p.Arg546Ter Uncertain significance ★ same residue
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

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-arg546 (accessed [today's date]).

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