Is EGF p.His365= (c.1095T>C) pathogenic?

EGF p.His365= (c.1095T>C) is classified Benign/Likely benign in EGF (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Common (popmax 6.23%, sas) — too common for a highly-penetrant pathogenic allele; Associated with renal hypomagnesemia 4.

What condition is associated with EGF p.His365= (c.1095T>C)?

EGF p.His365= (c.1095T>C) is associated with renal hypomagnesemia 4 (ClinVar).

EGF p.His365=

Q: How common is EGF p.His365= (c.1095T>C) in the general population?

EGF p.His365= (c.1095T>C) is common (popmax 6.23%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1095T>C · rs11568937 · VCV347232

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 6.23%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

renal hypomagnesemia 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.83 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.8	GERP -4.4
Overall
CADD	4.848	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.23% South Asian · 5,678/91,080 alleles

Filtering AF 6.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.04%

Overall 3.52% 56,774/1,613,974 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	6.23%	16
Middle Eastern	5.07%	20
Finnishnot grpmax-eligible	4.92%	20
Ashkenazi Jewishnot grpmax-eligible	4.69%	21
European (non-Finnish)	3.64%	27
Remaining individualsnot grpmax-eligible	3.47%	29
Admixed American	1.24%	80
African / African-American	0.534%	187
Amishnot grpmax-eligible	0.11%	912
East Asian	0.0178%	5,611

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.His365=
Coding: c.1095T>C
MANE Select: NM_001963
dbSNP: rs11568937
Type: single nucleotide variant
Location: chr4:109960895 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB
Residue 365: the egf-like 2; calcium-binding domain; a disulfide bond

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-p-his365 (accessed [today's date]).

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