Is FLT4 p.Lys516= (c.1548G>A) pathogenic?

FLT4 p.Lys516= (c.1548G>A) is classified Uncertain significance in FLT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). Absent from gnomAD v4.1; Associated with congenital heart defects, multiple types, 7.

What condition is associated with FLT4 p.Lys516= (c.1548G>A)?

FLT4 p.Lys516= (c.1548G>A) is associated with congenital heart defects, multiple types, 7 (ClinVar).

How common is FLT4 p.Lys516= (c.1548G>A) in the general population?

FLT4 p.Lys516= (c.1548G>A) is absent from gnomAD v4.1 (gnomAD).

FLT4 p.Lys516=

c.1548G>A · rs2127822309 · VCV3255144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

congenital heart defects, multiple types, 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.46	donor loss · deltas
Pangolin	Δ0.80	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.8	GERP 1.3, phastCons 1
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FLT4
Protein: p.Lys516=
Coding: c.1548G>A
MANE Select: NM_182925
dbSNP: rs2127822309
Type: single nucleotide variant
Location: chr5:180623935 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 516: a β-strand; a disulfide bond; a UniProt-annotated variant site (in chtd7); the ig-like c2-type 5 domain

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

Disease context

congenital heart defects, multiple types, 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FLT4 p.Arg318Ter Pathogenic/Likely pathogenic ★★ same condition
FLT4 p.Pro1137Leu Likely pathogenic ★★ same condition
FLT4 p.Arg1060Gln Uncertain significance ★★ ⚠ same condition
FLT4 p.Met1260Leu Uncertain significance ★★ ⚠ same condition
FLT4 p.Pro922Leu Uncertain significance ★★ ⚠ same condition
FLT4 c.1103+18C>T Benign/Likely benign ★★ same condition
FLT4 c.1103+20A>C Benign/Likely benign ★★ same condition
FLT4 c.1104-42T>C Benign ★★ 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-lys516 (accessed [today's date]).

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