Is KIT p.Pro34Leu (c.101C>T) pathogenic?

KIT p.Pro34Leu (c.101C>T) is classified Conflicting classifications of pathogenicity in KIT (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-05-26). AlphaMissense: likely benign (0.0647); Ultra-rare (popmax 0.0164%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Pro34Leu (c.101C>T)?

KIT p.Pro34Leu (c.101C>T) is associated with hereditary neoplastic syndrome, testicular cancer, gastrointestinal stromal tumor (ClinVar).

How common is KIT p.Pro34Leu (c.101C>T) in the general population?

KIT p.Pro34Leu (c.101C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about KIT p.Pro34Leu (c.101C>T)?

AlphaMissense predicts likely benign (score 0.0647) — an in-silico prediction, not a clinical call.

KIT p.Pro34Leu

c.101C>T · rs55755457 · VCV409788

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0647 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0647	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -9.11	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 -5.2	GERP -4.5
Regional constraint	o/e 0.67	unconstrained · MANE · 32 kb · p 3.4e-16 · regional, not allelic
Overall
CADD	0.023	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00994%

Overall 0.00967% 156/1,614,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.0122%	8,195
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Admixed American	0.00333%	30,002
East Asian	0.00223%	44,888
South Asian	0.0022%	45,540

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: KIT
Protein: p.Pro34Leu
Coding: c.101C>T
MANE Select: NM_000222
dbSNP: rs55755457
Type: single nucleotide variant
Location: chr4:54695545 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 34: the ig-like c2-type 1 domain

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: testicular cancer gastrointestinal stromal tumor

Similar variants

KIT p.Pro34= Benign/Likely benign ★★ same residue
KIT p.Pro34Gln Uncertain significance ★ ⚠ same residue
KIT p.Ala621Thr Pathogenic/Likely pathogenic ★★ same condition
KIT p.Asp820Tyr Pathogenic ★★ same condition
KIT p.Gln190Ter Pathogenic ★★ same condition
KIT p.Leu576Pro Pathogenic/Likely pathogenic ★★ same condition
KIT p.Lys642Glu Pathogenic ★★ same condition
KIT p.Trp557Arg Pathogenic/Likely pathogenic ★★ 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/kit-p-pro34leu (accessed [today's date]).

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