Is CA5A p.Val145Met (c.433G>A) pathogenic?

CA5A p.Val145Met (c.433G>A) is classified Uncertain significance in CA5A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-11). AlphaMissense: likely benign (0.1555); Ultra-rare (popmax 0.0247%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CA5A p.Val145Met (c.433G>A)?

CA5A p.Val145Met (c.433G>A) is associated with Inborn genetic diseases, hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (ClinVar).

How common is CA5A p.Val145Met (c.433G>A) in the general population?

CA5A p.Val145Met (c.433G>A) is ultra-rare (popmax 0.0247%, nfe) (gnomAD).

What do computational predictors say about CA5A p.Val145Met (c.433G>A)?

AlphaMissense predicts likely benign (score 0.1555) — an in-silico prediction, not a clinical call.

CA5A p.Val145Met

c.433G>A · rs138476706 · VCV1504037

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0247%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1555	likely benign
REVEL	0.625	indeterminate
SaProt	LLR -10.66	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.79, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 48 kb · p 0.027 · regional, not allelic
Overall
CADD	22.1	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 0.0247% European (non-Finnish) · 291/1,177,670 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0215%

Overall 0.0189% 304/1,611,426 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0247%	4,047
Remaining individualsnot grpmax-eligible	0.00802%	12,476
African / African-American	0.00534%	18,722
Admixed American	0.00333%	29,987
Finnishnot grpmax-eligible	0.00312%	32,017

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: CA5A
Protein: p.Val145Met
Coding: c.433G>A
MANE Select: NM_001739
dbSNP: rs138476706
Type: single nucleotide variant
Location: chr16:87904812 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.38
Residue 145: the alpha-carbonic anhydrase domain

Full CA5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Similar variants

CA5A p.Val145Ala Uncertain significance ★ ⚠ same residue
CA5A p.Arg32Ter Pathogenic ★★ same condition
CA5A p.Glu241Lys Pathogenic/Likely pathogenic ★★ same condition
CA5A p.Ala149Thr Uncertain significance ★★ ⚠ same condition
CA5A p.Ala208Val Uncertain significance ★★ ⚠ same condition
CA5A p.Ala261Val Uncertain significance ★★ ⚠ same condition
CA5A p.Arg26His Uncertain significance ★★ ⚠ same condition
CA5A p.Asp216Ala Uncertain significance ★★ ⚠ 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/ca5a-p-val145met (accessed [today's date]).

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