Is PC p.Pro1004Leu (c.3011C>T) pathogenic?

PC p.Pro1004Leu (c.3011C>T) is classified Uncertain significance in PC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-10). AlphaMissense: likely benign (0.0947); Very rare (popmax 0.00549%, sas).

How common is PC p.Pro1004Leu (c.3011C>T) in the general population?

PC p.Pro1004Leu (c.3011C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about PC p.Pro1004Leu (c.3011C>T)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

PC p.Pro1004Leu

c.3011C>T · VCV4912540

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.694	pathogenic-leaning
SaProt	LLR -9.05	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 23 kb · p 3.1e-25 · regional, not allelic
Overall
CADD	24.1	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 0.00549% South Asian · 5/91,090 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.0013% 21/1,614,194 alleles · very rare exomes 18/1,461,866 · genomes 3/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,218
Admixed American	0.00167%	60,026
Finnishnot grpmax-eligible	0.00156%	64,020
African / African-American	0.00133%	75,048
European (non-Finnish)	0.0011%	90,772

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.Pro1004Leu
Coding: c.3011C>T
MANE Select: NM_001040716
Type: single nucleotide variant
Location: chr11:66849747 (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 1004: an α-helix

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

Similar variants

PC p.Pro1004= 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-pro1004leu (accessed [today's date]).

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