Is CA4 p.Phe252Leu (c.756C>G) pathogenic?

CA4 p.Phe252Leu (c.756C>G) is classified Uncertain significance in CA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-21). AlphaMissense: likely pathogenic (0.9807); Very rare (popmax 0.00112%, sas).

How common is CA4 p.Phe252Leu (c.756C>G) in the general population?

CA4 p.Phe252Leu (c.756C>G) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about CA4 p.Phe252Leu (c.756C>G)?

AlphaMissense predicts likely pathogenic (score 0.9807) — an in-silico prediction, not a clinical call.

CA4 p.Phe252Leu

c.756C>G · rs2544527344 · VCV2782638

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9807	likely pathogenic · top 2% in CA4
REVEL	0.545	indeterminate
SaProt	LLR -7.47	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.7	GERP -1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 9,386 bp · p 0.89 · regional, not allelic
Overall
CADD	23.9	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 0.00112% South Asian · 1/89,236 alleles

Overall 6.24e-05% 1/1,602,416 alleles · very rare exomes 1/1,450,122 · genomes 0/152,294 · joint denominator

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.Phe252Leu
Coding: c.756C>G
MANE Select: NM_000717
dbSNP: rs2544527344
Type: single nucleotide variant
Location: chr17:60159241 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB
Residue 252: the alpha-carbonic anhydrase domain; an α-helix

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

Similar variants

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
CA4 p.Asp131Asn Uncertain significance ★★ ⚠ same type
CA4 p.Asp206Glu 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-phe252leu (accessed [today's date]).

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