Is FLT4 p.Asn149Asp (c.445A>G) pathogenic?

FLT4 p.Asn149Asp (c.445A>G) is classified Benign in FLT4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-26). AlphaMissense: likely benign (0.0974); Common (popmax 10.6%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about FLT4 p.Asn149Asp (c.445A>G)?

AlphaMissense predicts likely benign (score 0.0974) — an in-silico prediction, not a clinical call.

FLT4 p.Asn149Asp

Q: How common is FLT4 p.Asn149Asp (c.445A>G) in the general population?

FLT4 p.Asn149Asp (c.445A>G) is common (popmax 10.6%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.445A>G · rs34221241 · VCV263062

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0974 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.6%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0974	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -5.78	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 2.8	GERP -1.1, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 1,607 bp · p 1.9e-12 · regional, not allelic
Overall
CADD	15.84	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 10.6% European (non-Finnish) · 125,281/1,179,812 alleles

Filtering AF 10.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.5%

Overall 9.2% 148,404/1,612,212 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	15%	7
Finnishnot grpmax-eligible	11.9%	8
European (non-Finnish)grpmax	10.6%	9
Middle Eastern	8.64%	12
Remaining individualsnot grpmax-eligible	8.09%	12
Ashkenazi Jewishnot grpmax-eligible	6.6%	15
South Asian	4.63%	22
Admixed American	4.18%	24
African / African-American	1.73%	58
East Asian	0.0312%	3,206

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asn149Asp
Coding: c.445A>G
MANE Select: NM_182925
dbSNP: rs34221241
Type: single nucleotide variant
Location: chr5:180630293 (GRCh38)
Gene constraint: LOEUF 0.265 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 2 PDB
Residue 149: a UniProt-annotated variant site (in chtd7); a UniProt-annotated variant site (in)

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

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-asn149asp (accessed [today's date]).

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