Is VEGFA p.Pro259Ser (c.775C>T) pathogenic?

VEGFA p.Pro259Ser (c.775C>T) is classified Uncertain significance in VEGFA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: ambiguous (0.4802); Very rare (popmax 0.00167%, amr).

How common is VEGFA p.Pro259Ser (c.775C>T) in the general population?

VEGFA p.Pro259Ser (c.775C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about VEGFA p.Pro259Ser (c.775C>T)?

AlphaMissense predicts ambiguous (score 0.4802) — an in-silico prediction, not a clinical call.

VEGFA p.Pro259Ser

c.775C>T · VCV4603591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4802 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.4802	ambiguous
REVEL	0.126	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.24, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 7,087 bp · p 1.2e-05 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P79S vs ClinVar P259S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,012 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,614,110 alleles · very rare exomes 5/1,461,890 · genomes 0/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,012
European (non-Finnish)	0.000339%	295,007

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.Pro259Ser
Coding: c.775C>T
MANE Select: NM_003376
Type: single nucleotide variant
Location: chr6:43777585 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI 0.19 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.32 · 57 PDB

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-pro259ser (accessed [today's date]).

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