Is CA1 p.Ser49Arg (c.147T>A) pathogenic?

CA1 p.Ser49Arg (c.147T>A) is classified Uncertain significance in CA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: ambiguous (0.3517); Very rare (popmax 0.00017%, nfe).

How common is CA1 p.Ser49Arg (c.147T>A) in the general population?

CA1 p.Ser49Arg (c.147T>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CA1 p.Ser49Arg (c.147T>A)?

AlphaMissense predicts ambiguous (score 0.3517) — an in-silico prediction, not a clinical call.

CA1 p.Ser49Arg

c.147T>A · rs765511895 · VCV2605156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3517	ambiguous
REVEL	0.153	moderately benign-leaning
SaProt	LLR -9.25	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.73	GERP -3.8
Regional constraint	o/e 1.08	unconstrained · MANE · 13 kb · p 0.16 · regional, not allelic
Overall
CADD	0.38	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 0.00017% European (non-Finnish) · 2/1,179,754 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,854 alleles · very rare exomes 2/1,461,554 · genomes 0/152,300 · joint denominator

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: CA1
Protein: p.Ser49Arg
Coding: c.147T>A
MANE Select: NM_001128831
dbSNP: rs765511895
Type: single nucleotide variant
Location: chr8:85338340 (GRCh38)
Gene constraint: LOEUF 1.8 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.97 · 57 PDB
Residue 49: the alpha-carbonic anhydrase domain; a β-strand

Full CA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA1 p.Ala143Val Benign ★★ ⚠ same type
CA1 p.Ala167Val Benign ★★ same type
CA1 p.His120= Benign ★★ same type
CA1 p.Pro196Leu Benign ★★ same type
CA1 p.Ala154Gly Uncertain significance ★ ⚠ same type
CA1 p.Ala259Pro Uncertain significance ★ ⚠ same type
CA1 p.Arg228Cys Uncertain significance ★ ⚠ same type
CA1 p.Arg247Cys 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/ca1-p-ser49arg (accessed [today's date]).

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