Is FLT4 p.Ser393Arg (c.1179C>G) pathogenic?

FLT4 p.Ser393Arg (c.1179C>G) is classified Uncertain significance in FLT4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-08). AlphaMissense: likely pathogenic (0.7995); Ultra-rare (popmax 0.0853%, afr); Associated with FLT4-related disorder.

What condition is associated with FLT4 p.Ser393Arg (c.1179C>G)?

FLT4 p.Ser393Arg (c.1179C>G) is associated with FLT4-related disorder, lymphatic malformation 1 (ClinVar).

How common is FLT4 p.Ser393Arg (c.1179C>G) in the general population?

FLT4 p.Ser393Arg (c.1179C>G) is ultra-rare (popmax 0.0853%, afr) (gnomAD).

What do computational predictors say about FLT4 p.Ser393Arg (c.1179C>G)?

AlphaMissense predicts likely pathogenic (score 0.7995) — an in-silico prediction, not a clinical call.

FLT4 p.Ser393Arg

c.1179C>G · rs373516203 · VCV2634525

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7995 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0853%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

FLT4-related disorder

Computational evidence

Protein change
AlphaMissense	0.7995	likely pathogenic
REVEL	0.412	indeterminate
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -2.7
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	7.057	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 0.0853% African / African-American · 64/75,062 alleles

Filtering AF 0.0685% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0624%

Overall 0.00415% 67/1,612,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0853%	1,173
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	8.47e-05%	1,180,004

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.Ser393Arg
Coding: c.1179C>G
MANE Select: NM_182925
dbSNP: rs373516203
Type: single nucleotide variant
Location: chr5:180626190 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 393: an α-helix; 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

Also linked: lymphatic malformation 1

Similar variants

FLT4 p.Arg1041Gln Pathogenic/Likely pathogenic ★★ same condition
FLT4 p.Arg1041Trp Pathogenic/Likely pathogenic ★★ same condition
FLT4 p.Gly857Arg Pathogenic ★★ same condition
FLT4 p.Pro1137Leu Likely pathogenic ★★ same condition
FLT4 p.Ala702Ser Uncertain significance ★★ ⚠ same condition
FLT4 p.Ala855Thr Uncertain significance ★★ ⚠ same condition
FLT4 p.Arg1060Gln Uncertain significance ★★ ⚠ same condition
FLT4 p.Arg1070Cys Uncertain significance ★★ ⚠ 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-ser393arg (accessed [today's date]).

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