Is PCYT1A p.Pro44Ser (c.130C>T) pathogenic?

PCYT1A p.Pro44Ser (c.130C>T) is classified Uncertain significance in PCYT1A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). AlphaMissense: likely pathogenic (0.6022); Very rare (popmax 8.49e-05%, nfe).

How common is PCYT1A p.Pro44Ser (c.130C>T) in the general population?

PCYT1A p.Pro44Ser (c.130C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about PCYT1A p.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely pathogenic (score 0.6022) — an in-silico prediction, not a clinical call.

PCYT1A p.Pro44Ser

c.130C>T · rs2108771793 · VCV1396536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6022 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6022	likely pathogenic
REVEL	0.326	indeterminate
SaProt	LLR -13.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 22 kb · p 0.05 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,764 alleles

Overall 6.85e-05% 1/1,459,324 alleles · very rare

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: PCYT1A
Protein: p.Pro44Ser
Coding: c.130C>T
MANE Select: NM_001312673
dbSNP: rs2108771793
Type: single nucleotide variant
Location: chr3:196257875 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI 0.02 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.82

Full PCYT1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PCYT1A p.Pro44Arg Uncertain significance ★ ⚠ same residue
PCYT1A c.-10-2A>T Likely pathogenic ★★ same type
PCYT1A p.Ala99Val Pathogenic ★★ same type
PCYT1A p.Arg223Ser Pathogenic/Likely pathogenic ★★ same type
PCYT1A p.Arg75Ter Pathogenic ★★ same type
PCYT1A c.117+5G>A Uncertain significance ★★ same type
PCYT1A p.Ala18Val Uncertain significance ★★ ⚠ same type
PCYT1A p.Ala217Val 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/pcyt1a-p-pro44ser (accessed [today's date]).

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