Is EGF p.Ser16Arg (c.46A>C) pathogenic?

EGF p.Ser16Arg (c.46A>C) is classified Benign/Likely benign in EGF (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-16). AlphaMissense: ambiguous (0.4122); Low-frequency (popmax 2.74%, eas); Associated with renal hypomagnesemia 4.

What condition is associated with EGF p.Ser16Arg (c.46A>C)?

EGF p.Ser16Arg (c.46A>C) is associated with renal hypomagnesemia 4 (ClinVar).

How common is EGF p.Ser16Arg (c.46A>C) in the general population?

EGF p.Ser16Arg (c.46A>C) is low-frequency (popmax 2.74%, eas) (gnomAD).

What do computational predictors say about EGF p.Ser16Arg (c.46A>C)?

AlphaMissense predicts ambiguous (score 0.4122) — an in-silico prediction, not a clinical call.

EGF p.Ser16Arg

c.46A>C · rs11568849 · VCV347224

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4122 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.74%, eas)

Conditions

renal hypomagnesemia 4

Computational evidence

Protein change
AlphaMissense	0.4122	ambiguous
REVEL	0.403	indeterminate
SaProt	LLR -8.09	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.25	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.35	GERP -4.4, phastCons 0.004
Regional constraint	o/e 1.11	unconstrained · MANE · 28 kb · p 0.36 · regional, not allelic
Overall
CADD	6.196	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.74% East Asian · 1,231/44,868 alleles

Filtering AF 2.62% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.56%

Overall 0.192% 3,098/1,613,952 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	2.74%	36
Finnishnot grpmax-eligible	2.38%	42
Remaining individualsnot grpmax-eligible	0.165%	607
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,115
Middle Eastern	0.033%	3,029
European (non-Finnish)	0.0171%	5,841
African / African-American	0.016%	6,253
South Asian	0.00878%	11,385
Admixed American	0.00667%	14,995

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.Ser16Arg
Coding: c.46A>C
MANE Select: NM_001963
dbSNP: rs11568849
Type: single nucleotide variant
Location: chr4:109913381 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB
Residue 16: a UniProt-annotated variant site (in)

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.Ser16Thr 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-ser16arg (accessed [today's date]).

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