Is CA12 p.Pro26Arg (c.77C>G) pathogenic?

CA12 p.Pro26Arg (c.77C>G) is classified Likely benign in CA12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0993); Rare (popmax 0.269%, afr).

How common is CA12 p.Pro26Arg (c.77C>G) in the general population?

CA12 p.Pro26Arg (c.77C>G) is rare (popmax 0.269%, afr) (gnomAD).

What do computational predictors say about CA12 p.Pro26Arg (c.77C>G)?

AlphaMissense predicts likely benign (score 0.0993) — an in-silico prediction, not a clinical call.

CA12 p.Pro26Arg

c.77C>G · rs140995656 · VCV723354

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0993 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.269%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0993	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -7.98	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 8.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 55 kb · p 0.47 · regional, not allelic
Overall
CADD	24.9	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 0.269% African / African-American · 202/75,000 alleles

Filtering AF 0.239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.227%

Overall 0.014% 226/1,611,140 alleles · rare exomes 115/1,458,782 · genomes 111/152,358 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.269%	371
Remaining individualsnot grpmax-eligible	0.0209%	4,794
Admixed American	0.00669%	14,949
South Asian	0.00221%	45,155
European (non-Finnish)	0.000424%	235,738

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: CA12
Protein: p.Pro26Arg
Coding: c.77C>G
MANE Select: NM_001218
dbSNP: rs140995656
Type: single nucleotide variant
Location: chr15:63381644 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.50 · 40 PDB

Full CA12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA12 p.Pro26Leu Uncertain significance ★ ⚠ same residue
CA12 c.107-108T>C Benign ★★ same type
CA12 c.107-113G>A Benign ★★ same type
CA12 c.286+92G>A Benign ★★ same type
CA12 c.429+148G>A Benign ★★ same type
CA12 c.429+186C>G Benign ★★ same type
CA12 c.85+94C>G Benign ★★ same type
CA12 c.*234C>T 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/ca12-p-pro26arg (accessed [today's date]).

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