Is FLT1 p.Leu1269Phe (c.3805C>T) pathogenic?

FLT1 p.Leu1269Phe (c.3805C>T) is classified Uncertain significance in FLT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-13). AlphaMissense: likely benign (0.0768); Ultra-rare (popmax 0.0334%, nfe).

How common is FLT1 p.Leu1269Phe (c.3805C>T) in the general population?

FLT1 p.Leu1269Phe (c.3805C>T) is ultra-rare (popmax 0.0334%, nfe) (gnomAD).

What do computational predictors say about FLT1 p.Leu1269Phe (c.3805C>T)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

FLT1 p.Leu1269Phe

c.3805C>T · rs139333864 · VCV3095724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -7.54	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 0.91	GERP -1.6, phastCons 0.15
Regional constraint	o/e 0.90	unconstrained · MANE · 18 kb · p 0.052 · regional, not allelic
Overall
CADD	9.201	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 0.0334% European (non-Finnish) · 393/1,177,436 alleles

Filtering AF 0.0306% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.0249% 401/1,611,174 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0334%	2,996
Remaining individualsnot grpmax-eligible	0.0112%	8,915
African / African-American	0.00134%	74,862

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: FLT1
Protein: p.Leu1269Phe
Coding: c.3805C>T
MANE Select: NM_002019
dbSNP: rs139333864
Type: single nucleotide variant
Location: chr13:28306688 (GRCh38)
Gene constraint: LOEUF 0.379 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.86 · 12 PDB

Full FLT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FLT1 p.Asp6Asn Benign ★★ same type
FLT1 p.Cys107= Likely benign ★★ same type
FLT1 p.Ile548Met Likely benign ★★ ⚠ same type
FLT1 p.Leu492= Benign ★★ same type
FLT1 p.Met938Val Likely benign ★★ same type
FLT1 p.Pro1068= Benign ★★ same type
FLT1 p.Pro1201Leu Likely benign ★★ same type
FLT1 p.Thr260= 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/flt1-p-leu1269phe (accessed [today's date]).

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