Is KDR p.Ala1340Pro (c.4018G>C) pathogenic?

KDR p.Ala1340Pro (c.4018G>C) is classified Uncertain significance in KDR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely benign (0.071); Ultra-rare (popmax 0.0165%, mid).

How common is KDR p.Ala1340Pro (c.4018G>C) in the general population?

KDR p.Ala1340Pro (c.4018G>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about KDR p.Ala1340Pro (c.4018G>C)?

AlphaMissense predicts likely benign (score 0.071) — an in-silico prediction, not a clinical call.

KDR p.Ala1340Pro

c.4018G>C · VCV4042427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.071	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -5.57	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 0.35	GERP -0.23, phastCons 0.095
Regional constraint	o/e 1.16	unconstrained · MANE · 7,742 bp · p 0.027 · regional, not allelic
Overall
CADD	6.421	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 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,614,182 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
South Asian	0.0022%	45,539

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: KDR
Protein: p.Ala1340Pro
Coding: c.4018G>C
MANE Select: NM_002253
Type: single nucleotide variant
Location: chr4:55079994 (GRCh38)
Gene constraint: LOEUF 0.328 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.67 · 54 PDB

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

Similar variants

KDR p.Ala379Val Uncertain significance ★★ ⚠ same type
KDR p.Ala757Gly Uncertain significance ★★ ⚠ same type
KDR p.Asp832His Uncertain significance ★★ ⚠ same type
KDR p.Val416Ala Uncertain significance ★★ ⚠ same type
KDR p.Ala1030= Benign ★★ same type
KDR p.Ala532= Benign ★★ same type
KDR p.Arg842His Likely benign ★★ same type
KDR p.Cys482Arg Likely 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/kdr-p-ala1340pro (accessed [today's date]).

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