Is FLT4 p.Val335Ile (c.1003G>A) pathogenic?

FLT4 p.Val335Ile (c.1003G>A) is classified Uncertain significance in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely benign (0.1166); Very rare (popmax 0.005%, amr); Associated with FLT4-related disorder.

What condition is associated with FLT4 p.Val335Ile (c.1003G>A)?

FLT4 p.Val335Ile (c.1003G>A) is associated with FLT4-related disorder (ClinVar).

How common is FLT4 p.Val335Ile (c.1003G>A) in the general population?

FLT4 p.Val335Ile (c.1003G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about FLT4 p.Val335Ile (c.1003G>A)?

AlphaMissense predicts likely benign (score 0.1166) — an in-silico prediction, not a clinical call.

FLT4 p.Val335Ile

c.1003G>A · rs147644625 · VCV2629137

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1166 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FLT4-related disorder

Computational evidence

Protein change
AlphaMissense	0.1166	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -7.66	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 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 1,607 bp · p 1.9e-12 · regional, not allelic
Overall
CADD	22.3	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 0.005% Admixed American · 3/60,020 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000548% 8/1,460,142 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,007
East Asian	0.00223%	44,870
South Asian	0.0011%	91,064
European (non-Finnish)	0.000254%	393,229

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.Val335Ile
Coding: c.1003G>A
MANE Select: NM_182925
dbSNP: rs147644625
Type: single nucleotide variant
Location: chr5:180628982 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 335: a β-strand; a UniProt-annotated variant site (in chtd7); the ig-like c2-type 4 domain

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-val335ile (accessed [today's date]).

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