Is CA6 p.Leu7Pro (c.20T>C) pathogenic?

CA6 p.Leu7Pro (c.20T>C) is classified Uncertain significance in CA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-12). AlphaMissense: likely benign (0.1737); Ultra-rare (popmax 0.0245%, eas).

How common is CA6 p.Leu7Pro (c.20T>C) in the general population?

CA6 p.Leu7Pro (c.20T>C) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about CA6 p.Leu7Pro (c.20T>C)?

AlphaMissense predicts likely benign (score 0.1737) — an in-silico prediction, not a clinical call.

CA6 p.Leu7Pro

c.20T>C · rs763221471 · VCV3136145

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1737	likely benign
REVEL	0.565	indeterminate
SaProt	LLR -9.06	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 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 29 kb · p 0.8 · regional, not allelic
Overall
CADD	22.7	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 0.0245% East Asian · 11/44,876 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000806% 13/1,613,692 alleles · ultra-rare exomes 12/1,461,412 · genomes 1/152,280 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,080
African / African-American	0.00133%	75,010
European (non-Finnish)	8.48e-05%	1,179,636

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.Leu7Pro
Coding: c.20T>C
MANE Select: NM_001215
dbSNP: rs763221471
Type: single nucleotide variant
Location: chr1:8945906 (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-leu7pro (accessed [today's date]).

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