Is CA4 p.Arg14Trp (c.40C>T) pathogenic?

CA4 p.Arg14Trp (c.40C>T) is classified Conflicting classifications of pathogenicity in CA4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.2311); Ultra-rare (popmax 0.0177%, nfe); Associated with retinitis pigmentosa.

What condition is associated with CA4 p.Arg14Trp (c.40C>T)?

CA4 p.Arg14Trp (c.40C>T) is associated with retinitis pigmentosa, retinitis pigmentosa 17 (ClinVar).

How common is CA4 p.Arg14Trp (c.40C>T) in the general population?

CA4 p.Arg14Trp (c.40C>T) is ultra-rare (popmax 0.0177%, nfe) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CA4 p.Arg14Trp (c.40C>T)?

AlphaMissense predicts likely benign (score 0.2311) — an in-silico prediction, not a clinical call.

CA4 p.Arg14Trp

c.40C>T · rs104894559 · VCV17607

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2311 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.2311	likely benign
REVEL	0.359	indeterminate
SaProt	LLR -5.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.6
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	16.09	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 0.0177% European (non-Finnish) · 209/1,178,954 alleles

Filtering AF 0.0157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.015%

Overall 0.0167% 267/1,599,366 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0641%	1,559
Remaining individualsnot grpmax-eligible	0.0289%	3,455
European (non-Finnish)grpmax	0.0177%	5,641
African / African-American	0.00667%	14,985
Admixed American	0.00167%	59,914
South Asian	0.0011%	90,884

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg14Trp
Coding: c.40C>T
MANE Select: NM_000717
dbSNP: rs104894559
Type: single nucleotide variant
Location: chr17:60150074 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 14: a UniProt-annotated variant site (in rp17; abolishes interaction with slc4a4; impaired slc4a4 cotransporter activity stimulation)

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

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 17

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CA4 p.Gly87Glu Uncertain significance ★★ ⚠ same condition
CA4 p.Ile54Met Uncertain significance ★★ ⚠ same condition
CA4 p.Phe70Leu Uncertain significance ★★ ⚠ same condition
CA4 p.Pro227Leu Uncertain significance ★★ ⚠ same condition
CA4 c.-24G>C Benign ★★ same condition
CA4 c.-47C>G Benign ★★ same condition
CA4 p.Arg239Gln Benign ★★ same condition
CA4 p.Asn177Lys Benign/Likely benign ★★ ⚠ same condition

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-arg14trp (accessed [today's date]).

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