Is CA6 p.Leu13Pro (c.38T>C) pathogenic?

CA6 p.Leu13Pro (c.38T>C) is classified Uncertain significance in CA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: likely benign (0.1088); Very rare (popmax 0.00797%, nfe).

How common is CA6 p.Leu13Pro (c.38T>C) in the general population?

CA6 p.Leu13Pro (c.38T>C) is very rare (popmax 0.00797%, nfe) (gnomAD).

What do computational predictors say about CA6 p.Leu13Pro (c.38T>C)?

AlphaMissense predicts likely benign (score 0.1088) — an in-silico prediction, not a clinical call.

CA6 p.Leu13Pro

c.38T>C · VCV3262591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1088 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00797%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1088	likely benign
REVEL	0.513	indeterminate
SaProt	LLR -7.23	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 2.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 29 kb · p 0.8 · regional, not allelic
Overall
CADD	22.4	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 0.00797% European (non-Finnish) · 94/1,179,892 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00607% 98/1,613,858 alleles · very rare exomes 97/1,461,720 · genomes 1/152,138 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00797%	12,552
Remaining individualsnot grpmax-eligible	0.0064%	15,619

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: CA6
Protein: p.Leu13Pro
Coding: c.38T>C
MANE Select: NM_001215
Type: single nucleotide variant
Location: chr1:8945924 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49 · 1 PDB

Full CA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA6 p.Gly70= Benign ★★ same type
CA6 p.Ala33Val Uncertain significance ★ ⚠ same type
CA6 p.Arg255Cys Uncertain significance ★ ⚠ same type
CA6 p.Arg255Ser Uncertain significance ★ ⚠ same type
CA6 p.Arg265Gly Uncertain significance ★ ⚠ same type
CA6 p.Arg305Gly Uncertain significance ★ ⚠ same type
CA6 p.Arg96Gly Uncertain significance ★ ⚠ same type
CA6 p.Asn280Tyr 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/ca6-p-leu13pro (accessed [today's date]).

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