Is EGF p.Arg622Ter (c.1864C>T) pathogenic?

EGF p.Arg622Ter (c.1864C>T) is classified Uncertain significance in EGF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-17). Ultra-rare (popmax 0.0183%, amr); Associated with renal hypomagnesemia 4.

What condition is associated with EGF p.Arg622Ter (c.1864C>T)?

EGF p.Arg622Ter (c.1864C>T) is associated with renal hypomagnesemia 4 (ClinVar).

How common is EGF p.Arg622Ter (c.1864C>T) in the general population?

EGF p.Arg622Ter (c.1864C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

EGF p.Arg622Ter

c.1864C>T · rs759896124 · VCV1357481

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

renal hypomagnesemia 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 24
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Pangolin	Δ0.22	loss · gain 0.15 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP -0.091	GERP -1.6, phastCons 0.001
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,000 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00335% 54/1,613,824 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
African / African-American	0.00534%	18,728
Remaining individualsnot grpmax-eligible	0.0048%	20,823
European (non-Finnish)	0.0028%	35,753
East Asian	0.00223%	44,900
South Asian	0.0022%	45,541

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.Arg622Ter
Coding: c.1864C>T
MANE Select: NM_001963
dbSNP: rs759896124
Type: single nucleotide variant
Location: chr4:109976046 (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 p.Arg622Gln Uncertain significance ★ ⚠ same residue
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

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-arg622ter (accessed [today's date]).

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