Is CA4 p.Arg219His (c.656G>A) pathogenic?

CA4 p.Arg219His (c.656G>A) is classified Likely pathogenic in CA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: ambiguous (0.3818); Ultra-rare (popmax 0.0164%, mid).

How common is CA4 p.Arg219His (c.656G>A) in the general population?

CA4 p.Arg219His (c.656G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CA4 p.Arg219His (c.656G>A)?

AlphaMissense predicts ambiguous (score 0.3818) — an in-silico prediction, not a clinical call.

CA4 p.Arg219His

c.656G>A · rs769858478 · VCV1024689

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3818 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3818	ambiguous
REVEL	0.747	pathogenic-leaning
SaProt	LLR -13.79	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	32.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00118% 19/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.00878%	11,387
Admixed American	0.00167%	60,008
African / African-American	0.00134%	74,902
European (non-Finnish)	0.000678%	147,502

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: CA4
Protein: p.Arg219His
Coding: c.656G>A
MANE Select: NM_000717
dbSNP: rs769858478
Type: single nucleotide variant
Location: chr17:60158358 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 219: a disulfide bond; a UniProt-annotated variant site (in rp17; abolishes carbonate dehydratase activity; impaired slc4a4 cotransporter activity stimulation); the alpha-carbonic anhydrase domain; a β-strand

Full CA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA4 p.Arg219Cys Uncertain significance ★ ⚠ same residue
CA4 p.Arg219Ser Uncertain significance ⚠ same residue
CA4 c.745-9C>G Uncertain significance ★★ same type
CA4 p.Ala156Val Uncertain significance ★★ ⚠ same type
CA4 p.Ala308Ser Uncertain significance ★★ ⚠ same type
CA4 p.Arg279Pro Uncertain significance ★★ ⚠ same type
CA4 p.Arg50His Uncertain significance ★★ ⚠ same type
CA4 p.Arg50Ser 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/ca4-p-arg219his (accessed [today's date]).

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