Is EGF c.*446C>T pathogenic?

EGF c.446C>T is classified Likely benign in EGF (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Rare (popmax 0.281%, sas); Associated with renal hypomagnesemia 4.

What condition is associated with EGF c.*446C>T?

EGF c.*446C>T is associated with renal hypomagnesemia 4 (ClinVar).

How common is EGF c.*446C>T in the general population?

EGF c.*446C>T is rare (popmax 0.281%, sas) (gnomAD).

EGF c.*446C>T

rs534531408 · VCV347271

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.281%, sas)

Conditions

renal hypomagnesemia 4

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 -0.49	GERP -4.2
Non-coding constraint	Z 0.33	1 kb window · o/e 0.98 · regional · uncalibrated
Overall
CADD	0.745	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.281% South Asian · 32/11,398 alleles

Filtering AF 0.204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.021% 44/209,656 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.281%	356
African / African-American	0.0256%	3,910
European (non-Finnish)	0.00097%	103,080

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
Coding: c.*446C>T
MANE Select: NM_001963
dbSNP: rs534531408
Type: single nucleotide variant
Location: chr4:110011901 (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

Disease context

renal hypomagnesemia 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EGF c.2221+4C>T Uncertain significance ★★ same condition
EGF c.2858-11G>T Uncertain significance ★★ same condition
EGF c.-60C>T Uncertain significance ★★ same condition
EGF p.Ala1025Ser Uncertain significance ★★ ⚠ same condition
EGF p.Ala1037Val Uncertain significance ★★ ⚠ same condition
EGF p.Arg213Gln Uncertain significance ★★ ⚠ same condition
EGF p.Arg221Thr Uncertain significance ★★ ⚠ same condition
EGF p.Arg351Gln Uncertain significance ★★ ⚠ same condition

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-c-star-446c-t (accessed [today's date]).

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