Is CA4 p.Phe70Leu (c.210C>A) pathogenic?

CA4 p.Phe70Leu (c.210C>A) is classified Uncertain significance in CA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-19). AlphaMissense: likely pathogenic (0.8583); Absent from gnomAD v4.1; Associated with retinitis pigmentosa.

What condition is associated with CA4 p.Phe70Leu (c.210C>A)?

CA4 p.Phe70Leu (c.210C>A) is associated with retinitis pigmentosa (ClinVar).

How common is CA4 p.Phe70Leu (c.210C>A) in the general population?

CA4 p.Phe70Leu (c.210C>A) is absent from gnomAD v4.1 (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.Phe70Leu (c.210C>A)?

AlphaMissense predicts likely pathogenic (score 0.8583) — an in-silico prediction, not a clinical call.

CA4 p.Phe70Leu

c.210C>A · rs886053185 · VCV324227

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8583 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.8583	likely pathogenic
REVEL	0.381	indeterminate
SaProt	LLR -10.19	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 1.4	GERP 0.89, phastCons 0.81
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	21.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CA4
Protein: p.Phe70Leu
Coding: c.210C>A
MANE Select: NM_000717
dbSNP: rs886053185
Type: single nucleotide variant
Location: chr17:60156657 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 70: a disulfide bond; a β-strand; the alpha-carbonic anhydrase domain

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

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.Phe70Cys Uncertain significance ★★ ⚠ same residue
CA4 p.Ile54Met 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
CA4 p.Asn269= Likely benign ★★ same condition
CA4 p.Gln79Lys 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-phe70leu (accessed [today's date]).

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