Is EGF p.Ser869Phe (c.2606C>T) pathogenic?

EGF p.Ser869Phe (c.2606C>T) is classified Uncertain significance in EGF (ClinVar, Single submitter, 2 submitters; last evaluated 2023-07-13). AlphaMissense: likely benign (0.0951); Rare (popmax 0.168%, sas).

How common is EGF p.Ser869Phe (c.2606C>T) in the general population?

EGF p.Ser869Phe (c.2606C>T) is rare (popmax 0.168%, sas) (gnomAD).

What do computational predictors say about EGF p.Ser869Phe (c.2606C>T)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

EGF p.Ser869Phe

c.2606C>T · rs532628455 · VCV2720950

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.168%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -4.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -1.4, phastCons 0.023
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.00042 · regional, not allelic
Overall
CADD	11.79	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.168% South Asian · 153/91,038 alleles

Filtering AF 0.146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.138%

Overall 0.0109% 175/1,611,724 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.168%	595
Remaining individualsnot grpmax-eligible	0.0032%	31,206
European (non-Finnish)	0.0017%	58,899

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.Ser869Phe
Coding: c.2606C>T
MANE Select: NM_001963
dbSNP: rs532628455
Type: single nucleotide variant
Location: chr4:109987858 (GRCh38)
Gene constraint: LOEUF 0.741 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.66 · 13 PDB
Residue 869: the egf-like 6 domain

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

Similar variants

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
EGF p.Arg213Gln 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-ser869phe (accessed [today's date]).

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