Is EGFL7 p.Arg74His (c.221G>A) pathogenic?

EGFL7 p.Arg74His (c.221G>A) is classified Uncertain significance in EGFL7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.18); Ultra-rare (popmax 0.0935%, amr).

How common is EGFL7 p.Arg74His (c.221G>A) in the general population?

EGFL7 p.Arg74His (c.221G>A) is ultra-rare (popmax 0.0935%, amr) (gnomAD).

What do computational predictors say about EGFL7 p.Arg74His (c.221G>A)?

AlphaMissense predicts likely benign (score 0.18) — an in-silico prediction, not a clinical call.

EGFL7 p.Arg74His

c.221G>A · VCV4247216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.18 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0935%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.18	likely benign
REVEL	0.467	indeterminate
SaProt	LLR -11.53	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 4,000 bp · p 0.79 · regional, not allelic
Overall
CADD	31.0	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 0.0935% Admixed American · 56/59,896 alleles

Filtering AF 0.0739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0668%

Overall 0.00521% 84/1,611,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0935%	1,070
East Asian	0.00223%	44,798
European (non-Finnish)	0.00212%	47,174
Remaining individualsnot grpmax-eligible	0.0016%	62,322
South Asian	0.0011%	90,776

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: EGFL7
Protein: p.Arg74His
Coding: c.221G>A
MANE Select: NM_016215
Type: single nucleotide variant
Location: chr9:136669629 (GRCh38)
Gene constraint: LOEUF 1.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.11
Residue 74: the emi domain; a disulfide bond

Full EGFL7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EGFL7 p.Arg112Gln Benign/Likely benign ★★ same type
EGFL7 p.Ala101Asp Uncertain significance ★ ⚠ same type
EGFL7 p.Ala104Thr Uncertain significance ★ ⚠ same type
EGFL7 p.Ala143Thr Uncertain significance ★ ⚠ same type
EGFL7 p.Ala156Thr Uncertain significance ★ ⚠ same type
EGFL7 p.Ala87Thr Uncertain significance ★ ⚠ same type
EGFL7 p.Ala87Val Uncertain significance ★ ⚠ same type
EGFL7 p.Arg124Cys 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/egfl7-p-arg74his (accessed [today's date]).

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