Is FLT4 p.Leu159Val (c.475C>G) pathogenic?

FLT4 p.Leu159Val (c.475C>G) is classified Benign/Likely benign in FLT4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-01). AlphaMissense: likely benign (0.1148); Rare (popmax 0.253%, sas).

How common is FLT4 p.Leu159Val (c.475C>G) in the general population?

FLT4 p.Leu159Val (c.475C>G) is rare (popmax 0.253%, sas) (gnomAD).

What do computational predictors say about FLT4 p.Leu159Val (c.475C>G)?

AlphaMissense predicts likely benign (score 0.1148) — an in-silico prediction, not a clinical call.

FLT4 p.Leu159Val

c.475C>G · rs147634448 · VCV996261

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1148 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.253%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1148	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -8.77	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 3.2	GERP -0.65, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 1,607 bp · p 1.9e-12 · regional, not allelic
Overall
CADD	19.19	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 0.253% South Asian · 230/91,082 alleles

Filtering AF 0.226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.215%

Overall 0.0224% 362/1,612,700 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.253%	396
Middle Eastern	0.115%	866
Remaining individualsnot grpmax-eligible	0.0224%	4,463
Admixed American	0.0133%	7,502
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
European (non-Finnish)	0.00814%	12,291
Finnishnot grpmax-eligible	0.00638%	15,663

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.Leu159Val
Coding: c.475C>G
MANE Select: NM_182925
dbSNP: rs147634448
Type: single nucleotide variant
Location: chr5:180630263 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 159: a disulfide bond; a UniProt-annotated variant site (in chtd7); the ig-like c2-type 2 domain

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

Similar variants

FLT4 p.Arg1041Gln Pathogenic/Likely pathogenic ★★ same type
FLT4 p.Arg1041Trp Pathogenic/Likely pathogenic ★★ same type
FLT4 p.Arg318Ter Pathogenic/Likely pathogenic ★★ same type
FLT4 p.Gly1131Ser Pathogenic/Likely pathogenic ★★ same type
FLT4 p.Gly857Arg Pathogenic ★★ same type
FLT4 p.Pro1137Leu Likely pathogenic ★★ same type
FLT4 p.Ala702Ser Uncertain significance ★★ ⚠ same type
FLT4 p.Ala855Thr 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/flt4-p-leu159val (accessed [today's date]).

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