Is CA8 p.Ser147Phe (c.440C>T) pathogenic?

CA8 p.Ser147Phe (c.440C>T) is classified Uncertain significance in CA8 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-01). AlphaMissense: likely pathogenic (0.6651); Very rare (popmax 0.000424%, nfe).

How common is CA8 p.Ser147Phe (c.440C>T) in the general population?

CA8 p.Ser147Phe (c.440C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CA8 p.Ser147Phe (c.440C>T)?

AlphaMissense predicts likely pathogenic (score 0.6651) — an in-silico prediction, not a clinical call.

CA8 p.Ser147Phe

c.440C>T · rs1255274491 · VCV810290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6651	likely pathogenic
REVEL	0.444	indeterminate
SaProt	LLR -11.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 57 kb · p 0.00026 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000424% European (non-Finnish) · 5/1,179,768 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,568 alleles · very rare

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: CA8
Protein: p.Ser147Phe
Coding: c.440C>T
MANE Select: NM_004056
dbSNP: rs1255274491
Type: single nucleotide variant
Location: chr8:60232357 (GRCh38)
Gene constraint: LOEUF 0.698 · pLI 0.24 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.51 · 1 PDB
Residue 147: the alpha-carbonic anhydrase domain; a turn

Full CA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA8 p.Arg213Trp Uncertain significance ★★ ⚠ same type
CA8 p.Pro14Arg Uncertain significance ★★ ⚠ same type
CA8 p.Ser71Phe Uncertain significance ★★ ⚠ same type
CA8 c.100+154T>C Benign ★★ same type
CA8 c.100+19G>A Benign ★★ same type
CA8 c.100+37G>A Benign ★★ same type
CA8 c.100+81C>T Benign ★★ same type
CA8 c.100+85T>C 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/ca8-p-ser147phe (accessed [today's date]).

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