Is FLT4 p.Leu687Phe (c.2059C>T) pathogenic?

FLT4 p.Leu687Phe (c.2059C>T) is classified Uncertain significance in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-21). AlphaMissense: likely benign (0.1036); Very rare (popmax 0.00267%, afr); Associated with FLT4-related disorder.

What condition is associated with FLT4 p.Leu687Phe (c.2059C>T)?

FLT4 p.Leu687Phe (c.2059C>T) is associated with FLT4-related disorder (ClinVar).

How common is FLT4 p.Leu687Phe (c.2059C>T) in the general population?

FLT4 p.Leu687Phe (c.2059C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about FLT4 p.Leu687Phe (c.2059C>T)?

AlphaMissense predicts likely benign (score 0.1036) — an in-silico prediction, not a clinical call.

FLT4 p.Leu687Phe

c.2059C>T · rs139399208 · VCV2635972

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FLT4-related disorder

Computational evidence

Protein change
AlphaMissense	0.1036	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -6.21	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 7.2	GERP -0.007, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	24.7	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 0.00267% African / African-American · 2/74,940 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,612,688 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,470
Admixed American	0.00167%	59,998
European (non-Finnish)	8.47e-05%	1,179,966

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.Leu687Phe
Coding: c.2059C>T
MANE Select: NM_182925
dbSNP: rs139399208
Type: single nucleotide variant
Location: chr5:180621214 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 687: the ig-like c2-type 7 domain; 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.Leu687Val Likely benign ★★ same residue
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

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-leu687phe (accessed [today's date]).

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