Is VEGFA p.Ala74= (c.222C>G) pathogenic?

VEGFA p.Ala74= (c.222C>G) is classified Likely benign in VEGFA (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-21). Very rare (popmax 0.00533%, nfe).

How common is VEGFA p.Ala74= (c.222C>G) in the general population?

VEGFA p.Ala74= (c.222C>G) is very rare (popmax 0.00533%, nfe) (gnomAD).

VEGFA p.Ala74=

c.222C>G · rs1401245750 · VCV761761

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00533%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.021	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.005	GERP -0.69, phastCons 0.83
Overall
CADD	8.457	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% European (non-Finnish) · 61/1,145,456 alleles

Filtering AF 0.00422% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00383%

Overall 0.00408% 63/1,544,444 alleles · very rare exomes 62/1,392,346 · genomes 1/152,098 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00533%	18,778
Remaining individualsnot grpmax-eligible	0.00335%	29,883

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: VEGFA
Protein: p.Ala74=
Coding: c.222C>G
MANE Select: NM_003376
dbSNP: rs1401245750
Type: single nucleotide variant
Location: chr6:43770928 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.19 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.32 · 57 PDB
Residue 74: the 'disordered' region

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

Similar variants

VEGFA p.Asn371= Likely benign ★★ same type
VEGFA c.1034+36G>C Uncertain significance ★ ⚠ same type
VEGFA c.1034+42C>T Uncertain significance ★ ⚠ same type
VEGFA p.Ala123Glu Uncertain significance ★ same type
VEGFA p.Ala133Glu Uncertain significance ★ same type
VEGFA p.Ala79Asp Uncertain significance ★ same type
VEGFA p.Arg114Pro Uncertain significance ★ same type
VEGFA p.Arg171Gly 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/vegfa-p-ala74 (accessed [today's date]).

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