Is CA4 p.Phe72Leu (c.214T>C) pathogenic?

CA4 p.Phe72Leu (c.214T>C) is classified Uncertain significance in CA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: likely pathogenic (0.8); Absent from gnomAD v4.1; Associated with inherited retinal dystrophy.

What condition is associated with CA4 p.Phe72Leu (c.214T>C)?

CA4 p.Phe72Leu (c.214T>C) is associated with inherited retinal dystrophy (ClinVar).

How common is CA4 p.Phe72Leu (c.214T>C) in the general population?

CA4 p.Phe72Leu (c.214T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CA4 p.Phe72Leu (c.214T>C)?

AlphaMissense predicts likely pathogenic (score 0.8) — an in-silico prediction, not a clinical call.

CA4 p.Phe72Leu

c.214T>C · rs2544517206 · VCV3028471

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.8	likely pathogenic
REVEL	0.218	benign-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	20.1	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

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.Phe72Leu
Coding: c.214T>C
MANE Select: NM_000717
dbSNP: rs2544517206
Type: single nucleotide variant
Location: chr17:60156661 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 72: a β-strand; the alpha-carbonic anhydrase domain

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CA4 p.Asp268Asn Uncertain significance ★★ ⚠ same condition
CA4 p.Phe72del Uncertain significance ★★ same residue
CA4 p.Ala164= Benign/Likely benign ★★ same condition
CA4 p.Asn177Lys Benign/Likely benign ★★ ⚠ same condition
CA4 p.Asp161= Likely benign ★★ same condition
CA4 p.Lys145= Benign/Likely benign ★★ same condition
CA4 p.Pro287= Benign/Likely benign ★★ same condition
CA4 p.Ser119= 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-phe72leu (accessed [today's date]).

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