Is PC p.Arg644Trp (c.1930C>T) pathogenic?

PC p.Arg644Trp (c.1930C>T) is classified Uncertain significance in PC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-10). AlphaMissense: likely pathogenic (0.9201); Very rare (popmax 0.00223%, eas).

How common is PC p.Arg644Trp (c.1930C>T) in the general population?

PC p.Arg644Trp (c.1930C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PC p.Arg644Trp (c.1930C>T)?

AlphaMissense predicts likely pathogenic (score 0.9201) — an in-silico prediction, not a clinical call.

PC p.Arg644Trp

c.1930C>T · VCV4912547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9201	likely pathogenic
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -13.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 0.67, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 23 kb · p 3.1e-25 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,884 alleles

Overall 0.000124% 2/1,614,110 alleles · very rare exomes 2/1,461,840 · genomes 0/152,270 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
African / African-American	0.00133%	75,010

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: PC
Protein: p.Arg644Trp
Coding: c.1930C>T
MANE Select: NM_001040716
Type: single nucleotide variant
Location: chr11:66851842 (GRCh38)
Gene constraint: LOEUF 0.539 · pLI 0.07 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.53 · 10 PDB
Residue 644: a β-strand; a binding site; the pyruvate carboxyltransferase domain

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

Similar variants

PC p.Arg644= Likely benign ★ same residue
PC c.1368+1G>A Likely pathogenic ★★ same type
PC c.1826-1G>C Likely pathogenic ★★ same type
PC c.1983-116C>T Likely pathogenic ★★ same type
PC c.633+2T>C Likely pathogenic ★★ same type
PC p.Ala610Thr Pathogenic ★★ same type
PC p.Ala812Asp Likely pathogenic ★★ same type
PC p.Arg18Ter 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/pc-p-arg644trp (accessed [today's date]).

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