Is KEL p.Pro375Thr (c.1123C>A) pathogenic?

KEL p.Pro375Thr (c.1123C>A) is classified Uncertain significance in KEL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-07). AlphaMissense: likely benign (0.1461); Very rare (popmax 0.00668%, afr); Associated with vein of Galen aneurysm.

What condition is associated with KEL p.Pro375Thr (c.1123C>A)?

KEL p.Pro375Thr (c.1123C>A) is associated with vein of Galen aneurysm (ClinVar).

How common is KEL p.Pro375Thr (c.1123C>A) in the general population?

KEL p.Pro375Thr (c.1123C>A) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about KEL p.Pro375Thr (c.1123C>A)?

AlphaMissense predicts likely benign (score 0.1461) — an in-silico prediction, not a clinical call.

KEL p.Pro375Thr

c.1123C>A · VCV3288014

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

vein of Galen aneurysm

Computational evidence

Protein change
AlphaMissense	0.1461	likely benign
REVEL	0.469	indeterminate
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.95 · regional, not allelic
Overall
CADD	25.7	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 0.00668% African / African-American · 5/74,896 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000805% 13/1,613,960 alleles · very rare exomes 8/1,461,854 · genomes 5/152,106 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,979
European (non-Finnish)	0.000678%	147,501

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: KEL
Protein: p.Pro375Thr
Coding: c.1123C>A
MANE Select: NM_000420
Type: single nucleotide variant
Location: chr7:142952589 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.46
Residue 375: the peptidase m13 domain

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

Disease context

vein of Galen aneurysm — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KEL p.Ala424Val Uncertain significance ★ ⚠ same condition
KEL p.Ser544Ter Uncertain significance ★ same condition
KEL p.Arg516= Benign ★★ same type
KEL p.Leu335= Likely benign ★★ same type
KEL p.Leu597Pro Benign ★★ same type
KEL p.Phe324= Benign ★★ same type
KEL c.400+1G>A Pathogenic ★ same type
KEL p.Ala148Gly 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/kel-p-pro375thr (accessed [today's date]).

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