Is EGF p.Asn749= (c.2247C>T) pathogenic?

EGF p.Asn749= (c.2247C>T) is classified Likely benign in EGF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). Very rare (popmax 0.00401%, afr).

How common is EGF p.Asn749= (c.2247C>T) in the general population?

EGF p.Asn749= (c.2247C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

EGF p.Asn749=

c.2247C>T · VCV4016640

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00401%, 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 -6.5	GERP -4.1
Overall
CADD	4.993	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,886 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00235% 38/1,613,924 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,344
African / African-Americangrpmax	0.00401%	24,962
South Asian	0.00329%	30,361
European (non-Finnish)	0.00237%	42,141
Remaining individualsnot grpmax-eligible	0.0016%	62,486

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asn749=
Coding: c.2247C>T
MANE Select: NM_001963
Type: single nucleotide variant
Location: chr4:109980851 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB
Residue 749: the egf-like 5 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-asn749 (accessed [today's date]).

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