Is FLT4 p.Ser174Leu (c.521C>T) pathogenic?

FLT4 p.Ser174Leu (c.521C>T) is classified Conflicting classifications of pathogenicity in FLT4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2021-07-29). AlphaMissense: likely benign (0.0975); Ultra-rare (popmax 0.0186%, nfe); Associated with lymphedema.

What condition is associated with FLT4 p.Ser174Leu (c.521C>T)?

FLT4 p.Ser174Leu (c.521C>T) is associated with lymphedema (ClinVar).

How common is FLT4 p.Ser174Leu (c.521C>T) in the general population?

FLT4 p.Ser174Leu (c.521C>T) is ultra-rare (popmax 0.0186%, nfe) (gnomAD).

What do computational predictors say about FLT4 p.Ser174Leu (c.521C>T)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

FLT4 p.Ser174Leu

c.521C>T · rs773696166 · VCV1100678

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphedema

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -6.97	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 5.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 1,607 bp · p 1.9e-12 · regional, not allelic
Overall
CADD	20.9	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 0.0186% European (non-Finnish) · 219/1,179,984 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.014% 226/1,612,510 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0186%	5,388
African / African-American	0.00401%	24,962
Remaining individualsnot grpmax-eligible	0.0032%	31,232
Finnishnot grpmax-eligible	0.0016%	62,624
South Asian	0.0011%	91,070

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.Ser174Leu
Coding: c.521C>T
MANE Select: NM_182925
dbSNP: rs773696166
Type: single nucleotide variant
Location: chr5:180630098 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 174: 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

Disease context

lymphedema — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-ser174leu (accessed [today's date]).

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