Is FLT4 p.Met1186Val (c.3556A>G) pathogenic?

FLT4 p.Met1186Val (c.3556A>G) is classified Uncertain significance in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.0586); Ultra-rare (popmax 0.03%, amr); Associated with Inborn genetic diseases.

What condition is associated with FLT4 p.Met1186Val (c.3556A>G)?

FLT4 p.Met1186Val (c.3556A>G) is associated with Inborn genetic diseases (ClinVar).

How common is FLT4 p.Met1186Val (c.3556A>G) in the general population?

FLT4 p.Met1186Val (c.3556A>G) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about FLT4 p.Met1186Val (c.3556A>G)?

AlphaMissense predicts likely benign (score 0.0586) — an in-silico prediction, not a clinical call.

FLT4 p.Met1186Val

c.3556A>G · rs762445498 · VCV2468053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0586 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0586	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -5.13	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 -3.4	GERP -2.8
Regional constraint	o/e 0.95	unconstrained · MANE · 9,843 bp · p 0.36 · regional, not allelic
Overall
CADD	0.036	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 0.03% Admixed American · 18/59,974 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00521% 84/1,613,672 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,332
European (non-Finnish)	0.00542%	18,437
Remaining individualsnot grpmax-eligible	0.0016%	62,472
African / African-American	0.00134%	74,832

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.Met1186Val
Coding: c.3556A>G
MANE Select: NM_182925
dbSNP: rs762445498
Type: single nucleotide variant
Location: chr5:180611461 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 1186: a UniProt-annotated variant site (in chtd7)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FLT4 p.Gly1131Ser Pathogenic/Likely pathogenic ★★ same condition
FLT4 p.Ala702Ser Uncertain significance ★★ ⚠ same condition
FLT4 p.Arg1189His Uncertain significance ★★ ⚠ same condition
FLT4 p.Glu207Lys Uncertain significance ★★ ⚠ same condition
FLT4 p.Glu365Lys Uncertain significance ★★ ⚠ same condition
FLT4 p.Gly4Ala Uncertain significance ★★ ⚠ same condition
FLT4 p.Met1260Leu Uncertain significance ★★ ⚠ same condition
FLT4 p.Pro922Leu 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-met1186val (accessed [today's date]).

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