Is PROC p.Ala43Thr (c.127G>A) pathogenic?

PROC p.Ala43Thr (c.127G>A) is classified Conflicting classifications of pathogenicity in PROC (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-12-19). AlphaMissense: likely benign (0.1596); Ultra-rare (popmax 0.011%, nfe); Associated with PROC-related disorder.

What condition is associated with PROC p.Ala43Thr (c.127G>A)?

PROC p.Ala43Thr (c.127G>A) is associated with PROC-related disorder, thrombophilia due to protein C deficiency, autosomal dominant (ClinVar).

How common is PROC p.Ala43Thr (c.127G>A) in the general population?

PROC p.Ala43Thr (c.127G>A) is ultra-rare (popmax 0.011%, nfe) (gnomAD).

What do computational predictors say about PROC p.Ala43Thr (c.127G>A)?

AlphaMissense predicts likely benign (score 0.1596) — an in-silico prediction, not a clinical call.

PROC p.Ala43Thr

c.127G>A · rs767626189 · VCV1330289

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1596 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PROC-related disorder

Computational evidence

Protein change
AlphaMissense	0.1596	likely benign
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -11.72	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	22.9	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 0.011% European (non-Finnish) · 130/1,179,934 alleles

Filtering AF 0.00944% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00818% 132/1,613,786 alleles · ultra-rare exomes 126/1,461,566 · genomes 6/152,220 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.011%	9,076
Admixed American	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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: PROC
Protein: p.Ala43Thr
Coding: c.127G>A
MANE Select: NM_000312
dbSNP: rs767626189
Type: single nucleotide variant
Location: chr2:127421339 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 43: a UniProt-annotated variant site (in); the gla domain

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

Disease context

PROC-related disorder

Also linked: thrombophilia due to protein C deficiency, autosomal dominant

Similar variants

PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg199Ter Pathogenic ★★ same condition
PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg220Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
PROC p.Arg271Trp Pathogenic/Likely pathogenic ★★ same condition
PROC p.Arg272Cys Pathogenic/Likely pathogenic ★★ 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/proc-p-ala43thr (accessed [today's date]).

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