Is FLT4 p.Val193Met (c.577G>A) pathogenic?

FLT4 p.Val193Met (c.577G>A) is classified Uncertain significance in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-24). AlphaMissense: ambiguous (0.488); Very rare (popmax 0.00133%, afr); Associated with FLT4-related disorder.

What condition is associated with FLT4 p.Val193Met (c.577G>A)?

FLT4 p.Val193Met (c.577G>A) is associated with FLT4-related disorder (ClinVar).

How common is FLT4 p.Val193Met (c.577G>A) in the general population?

FLT4 p.Val193Met (c.577G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about FLT4 p.Val193Met (c.577G>A)?

AlphaMissense predicts ambiguous (score 0.488) — an in-silico prediction, not a clinical call.

FLT4 p.Val193Met

c.577G>A · rs778477946 · VCV2629109

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

FLT4-related disorder

Computational evidence

Protein change
AlphaMissense	0.488	ambiguous
REVEL	0.188	benign-leaning
SaProt	LLR -12.91	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	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	25.0	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 0.00133% African / African-American · 1/74,914 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,612,664 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,914
South Asian	0.0011%	91,084
European (non-Finnish)	0.000169%	589,998

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.Val193Met
Coding: c.577G>A
MANE Select: NM_182925
dbSNP: rs778477946
Type: single nucleotide variant
Location: chr5:180630042 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 193: 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

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-val193met (accessed [today's date]).

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