Is PROC p.Ala388Val (c.1163C>T) pathogenic?

PROC p.Ala388Val (c.1163C>T) is classified Conflicting classifications of pathogenicity in PROC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.8786); Very rare (popmax 0.000254%, nfe); Associated with Reduced protein C activity.

How common is PROC p.Ala388Val (c.1163C>T) in the general population?

PROC p.Ala388Val (c.1163C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PROC p.Ala388Val (c.1163C>T)?

AlphaMissense predicts likely pathogenic (score 0.8786) — an in-silico prediction, not a clinical call.

PROC p.Ala388Val

Q: What condition is associated with PROC p.Ala388Val (c.1163C>T)?

PROC p.Ala388Val (c.1163C>T) is associated with Reduced protein C activity, thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive (ClinVar).

c.1163C>T · rs769277939 · VCV627215

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Reduced protein C activity

Computational evidence

Protein change
AlphaMissense	0.8786	likely pathogenic
REVEL	0.928	moderately pathogenic-leaning
SaProt	LLR -11.14	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	29.6	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 0.000254% European (non-Finnish) · 3/1,180,022 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,272 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	0.000254%	393,340

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala388Val
Coding: c.1163C>T
MANE Select: NM_000312
dbSNP: rs769277939
Type: single nucleotide variant
Location: chr2:127428723 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 388: a UniProt-annotated variant site (in patients with proc deficiency); a β-strand; the peptidase s1 domain

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

Disease context

Reduced protein C activity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

PROC p.Ala388Glu Uncertain significance ★ ⚠ same residue
PROC p.Ala388Gly Uncertain significance ★ ⚠ same residue
PROC p.Ala388= Likely benign ★ same residue
PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same condition
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

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-ala388val (accessed [today's date]).

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