Is CA8 p.Arg213Trp (c.637C>T) pathogenic?

CA8 p.Arg213Trp (c.637C>T) is classified Uncertain significance in CA8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.6739); Ultra-rare (popmax 0.0165%, mid).

How common is CA8 p.Arg213Trp (c.637C>T) in the general population?

CA8 p.Arg213Trp (c.637C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CA8 p.Arg213Trp (c.637C>T)?

AlphaMissense predicts likely pathogenic (score 0.6739) — an in-silico prediction, not a clinical call.

CA8 p.Arg213Trp

c.637C>T · VCV4541375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6739 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6739	likely pathogenic
REVEL	0.572	indeterminate
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.1	GERP 0.34, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 57 kb · p 0.00026 · regional, not allelic
Overall
CADD	26.3	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0015%

Overall 0.0023% 37/1,610,654 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
African / African-American	0.004%	24,995
Admixed American	0.00333%	30,010
European (non-Finnish)	0.00246%	40,580
Remaining individualsnot grpmax-eligible	0.0016%	62,390
South Asian	0.0011%	91,034

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.Arg213Trp
Coding: c.637C>T
MANE Select: NM_004056
Type: single nucleotide variant
Location: chr8:60222750 (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 213: the alpha-carbonic anhydrase domain

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

Similar variants

CA8 p.Arg213Gln Uncertain significance ★ ⚠ same residue
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-arg213trp (accessed [today's date]).

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