Is PCCB p.Val299Phe (c.895G>T) pathogenic?

PCCB p.Val299Phe (c.895G>T) is classified Uncertain significance in PCCB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-11). AlphaMissense: ambiguous (0.3655); Very rare (popmax 0.000169%, nfe).

How common is PCCB p.Val299Phe (c.895G>T) in the general population?

PCCB p.Val299Phe (c.895G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about PCCB p.Val299Phe (c.895G>T)?

AlphaMissense predicts ambiguous (score 0.3655) — an in-silico prediction, not a clinical call.

PCCB p.Val299Phe

c.895G>T · rs794727960 · VCV199033

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3655	ambiguous
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -11.14	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 80 kb · p 0.017 · regional, not allelic
Overall
CADD	26.7	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) · 2/1,179,962 alleles

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

Overall 0.000124% 2/1,614,070 alleles · very rare exomes 2/1,461,794 · 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: PCCB
Protein: p.Val299Phe
Coding: c.895G>T
MANE Select: NM_000532
dbSNP: rs794727960
Type: single nucleotide variant
Location: chr3:136301040 (GRCh38)
Gene constraint: LOEUF 0.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.59 · 24 PDB
Residue 299: the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region

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

Similar variants

PCCB c.1199-1G>A Pathogenic/Likely pathogenic ★★ same type
PCCB c.1199-2A>G Pathogenic ★★ same type
PCCB c.1398+1G>C Pathogenic/Likely pathogenic ★★ same type
PCCB c.1398+1G>T Pathogenic/Likely pathogenic ★★ same type
PCCB c.1498+2T>C Pathogenic ★★ same type
PCCB c.1499-1G>C Pathogenic/Likely pathogenic ★★ same type
PCCB c.183+1G>A Pathogenic/Likely pathogenic ★★ same type
PCCB c.183+5G>A Pathogenic/Likely pathogenic ★★ 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/pccb-p-val299phe (accessed [today's date]).

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