Is FLT4 p.Val765Met (c.2293G>A) pathogenic?

FLT4 p.Val765Met (c.2293G>A) is classified Uncertain significance in FLT4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-02-20). AlphaMissense: ambiguous (0.463); Very rare (popmax 8.48e-05%, nfe); Associated with FLT4-related disorder.

What condition is associated with FLT4 p.Val765Met (c.2293G>A)?

FLT4 p.Val765Met (c.2293G>A) is associated with FLT4-related disorder (ClinVar).

How common is FLT4 p.Val765Met (c.2293G>A) in the general population?

FLT4 p.Val765Met (c.2293G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about FLT4 p.Val765Met (c.2293G>A)?

AlphaMissense predicts ambiguous (score 0.463) — an in-silico prediction, not a clinical call.

FLT4 p.Val765Met

c.2293G>A · rs2127813184 · VCV3061399

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

FLT4-related disorder

Computational evidence

Protein change
AlphaMissense	0.463	ambiguous
REVEL	0.757	pathogenic-leaning
SaProt	LLR -13.95	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	26.4	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 8.48e-05% European (non-Finnish) · 1/1,178,588 alleles

Overall 6.86e-05% 1/1,457,270 alleles · very rare

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: FLT4
Protein: p.Val765Met
Coding: c.2293G>A
MANE Select: NM_182925
dbSNP: rs2127813184
Type: single nucleotide variant
Location: chr5:180620882 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 765: a UniProt-annotated variant site (in chtd7)

Full FLT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

FLT4-related disorder

Similar variants

FLT4 p.Gly857Arg Pathogenic ★★ same condition
FLT4 p.Pro1137Leu Likely pathogenic ★★ same condition
FLT4 p.Ser393Arg Uncertain significance ★★ ⚠ same condition
FLT4 c.2168-1G>A Likely pathogenic ★ same condition
FLT4 p.Arg1041Gly Likely pathogenic ★ same condition
FLT4 p.Gln1020Leu Pathogenic ★ same condition
FLT4 p.Gln1179Ter Pathogenic ★ same condition
FLT4 p.Gly1276Glu Likely pathogenic ★ same condition

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/flt4-p-val765met (accessed [today's date]).

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