Is FLT3 p.Ser446Leu (c.1337C>T) pathogenic?

FLT3 p.Ser446Leu (c.1337C>T) is classified Likely benign in FLT3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-10-07). AlphaMissense: likely benign (0.0899); Rare (popmax 0.322%, sas); Associated with FLT3-related disorder.

What condition is associated with FLT3 p.Ser446Leu (c.1337C>T)?

FLT3 p.Ser446Leu (c.1337C>T) is associated with FLT3-related disorder (ClinVar).

How common is FLT3 p.Ser446Leu (c.1337C>T) in the general population?

FLT3 p.Ser446Leu (c.1337C>T) is rare (popmax 0.322%, sas) (gnomAD).

What do computational predictors say about FLT3 p.Ser446Leu (c.1337C>T)?

AlphaMissense predicts likely benign (score 0.0899) — an in-silico prediction, not a clinical call.

FLT3 p.Ser446Leu

c.1337C>T · rs201256911 · VCV3047481

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0899 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.322%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

FLT3-related disorder

Computational evidence

Protein change
AlphaMissense	0.0899	likely benign
REVEL	0.348	indeterminate
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 96 kb · p 0.00044 · regional, not allelic
Overall
CADD	17.88	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 0.322% South Asian · 293/91,056 alleles

Filtering AF 0.291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.28%

Overall 0.0203% 327/1,614,010 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.322%	311
Remaining individualsnot grpmax-eligible	0.024%	4,167
Middle Eastern	0.0165%	6,060
Admixed American	0.00167%	59,986
European (non-Finnish)	0.00136%	73,748
African / African-American	0.00133%	75,014

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: FLT3
Protein: p.Ser446Leu
Coding: c.1337C>T
MANE Select: NM_004119
dbSNP: rs201256911
Type: single nucleotide variant
Location: chr13:28036016 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.19 · 11 PDB

Full FLT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

FLT3-related disorder

Similar variants

FLT3 p.Ala813= Likely benign same condition
FLT3 p.Val95= Likely benign same condition
FLT3 p.Tyr597_Glu598insAspValAspPheArgGluTyr Pathogenic ★ same condition
FLT3 c.1205+56C>T Benign ★★ same type
FLT3 c.1310-3T>C Benign ★★ same type
FLT3 c.1418+75A>G Benign ★★ same type
FLT3 c.1418+81A>G Benign ★★ same type
FLT3 c.1419-15T>C Benign ★★ 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/flt3-p-ser446leu (accessed [today's date]).

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