Is CA14 p.Leu134Phe (c.400C>T) pathogenic?

CA14 p.Leu134Phe (c.400C>T) is classified Uncertain significance in CA14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: ambiguous (0.4827); Very rare (popmax 0.00833%, amr).

How common is CA14 p.Leu134Phe (c.400C>T) in the general population?

CA14 p.Leu134Phe (c.400C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about CA14 p.Leu134Phe (c.400C>T)?

AlphaMissense predicts ambiguous (score 0.4827) — an in-silico prediction, not a clinical call.

CA14 p.Leu134Phe

c.400C>T · VCV4647384

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Computational evidence

Protein change
AlphaMissense	0.4827	ambiguous
REVEL	0.562	indeterminate
SaProt	LLR -12.32	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,527 bp · p 0.45 · regional, not allelic
Overall
CADD	29.1	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

Grpmax group 0.00833% Admixed American · 5/60,026 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000411% 6/1,459,862 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,005
East Asian	0.00223%	44,876

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: CA14
Protein: p.Leu134Phe
Coding: c.400C>T
MANE Select: NM_012113
Type: single nucleotide variant
Location: chr1:150262525 (GRCh38)
Gene constraint: LOEUF 1.167 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.11 · 2 PDB
Residue 134: a disulfide bond; a β-strand; the alpha-carbonic anhydrase domain

Full CA14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA14 p.Glu149= Benign ★★ same type
CA14 p.Ala158Gly Uncertain significance ★ ⚠ same type
CA14 p.Ala173Val Uncertain significance ★ ⚠ same type
CA14 p.Arg101Gln Uncertain significance ★ ⚠ same type
CA14 p.Arg211Gly Uncertain significance ★ ⚠ same type
CA14 p.Arg211His Uncertain significance ★ ⚠ same type
CA14 p.Arg232Gly Uncertain significance ★ ⚠ same type
CA14 p.Arg264Gln 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/ca14-p-leu134phe (accessed [today's date]).

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