Is CA7 p.Leu166Phe (c.496C>T) pathogenic?

CA7 p.Leu166Phe (c.496C>T) is classified Uncertain significance in CA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-16). AlphaMissense: ambiguous (0.4555); Very rare (popmax 0.000169%, nfe).

How common is CA7 p.Leu166Phe (c.496C>T) in the general population?

CA7 p.Leu166Phe (c.496C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CA7 p.Leu166Phe (c.496C>T)?

AlphaMissense predicts ambiguous (score 0.4555) — an in-silico prediction, not a clinical call.

CA7 p.Leu166Phe

c.496C>T · rs2544022211 · VCV2347280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4555 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4555	ambiguous
REVEL	0.573	indeterminate
SaProt	LLR -9.92	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 9,007 bp · p 3.9e-13 · regional, not allelic
Overall
CADD	24.2	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 0.000169% European (non-Finnish) · 2/1,179,988 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,080 alleles · very rare exomes 2/1,461,804 · genomes 0/152,276 · 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: CA7
Protein: p.Leu166Phe
Coding: c.496C>T
MANE Select: NM_005182
dbSNP: rs2544022211
Type: single nucleotide variant
Location: chr16:66851706 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 97.15 · 13 PDB
Residue 166: the alpha-carbonic anhydrase domain; an α-helix

Full CA7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA7 p.Ala165Val Uncertain significance ★ ⚠ same type
CA7 p.Ala55Asp Uncertain significance ★ ⚠ same type
CA7 p.Ala55Gly Uncertain significance ★ ⚠ same type
CA7 p.Arg161Leu Uncertain significance ★ ⚠ same type
CA7 p.Arg191Trp Uncertain significance ★ ⚠ same type
CA7 p.Arg215Trp Uncertain significance ★ ⚠ same type
CA7 p.Arg256His Uncertain significance ★ ⚠ same type
CA7 p.Arg263Gln 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/ca7-p-leu166phe (accessed [today's date]).

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