Is EGF p.Arg403Cys (c.1207C>T) pathogenic?

EGF p.Arg403Cys (c.1207C>T) is classified Uncertain significance in EGF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). AlphaMissense: likely benign (0.2711); Very rare (popmax 0.00668%, eas).

How common is EGF p.Arg403Cys (c.1207C>T) in the general population?

EGF p.Arg403Cys (c.1207C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about EGF p.Arg403Cys (c.1207C>T)?

AlphaMissense predicts likely benign (score 0.2711) — an in-silico prediction, not a clinical call.

EGF p.Arg403Cys

c.1207C>T · rs776647507 · VCV2176401

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2711 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2711	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -10.70	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.7	GERP -4.1, phastCons 0.64
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.00042 · regional, not allelic
Overall
CADD	17.71	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 0.00668% East Asian · 3/44,892 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000868% 14/1,613,666 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,964
Remaining individualsnot grpmax-eligible	0.0032%	31,229
South Asian	0.0022%	45,542
Admixed American	0.00167%	59,962
European (non-Finnish)	0.000509%	196,630

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.Arg403Cys
Coding: c.1207C>T
MANE Select: NM_001963
dbSNP: rs776647507
Type: single nucleotide variant
Location: chr4:109961880 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB
Residue 403: the egf-like 3 domain; a disulfide bond

Full EGF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EGF p.Arg403His Uncertain significance ★ ⚠ same residue
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

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-arg403cys (accessed [today's date]).

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