Is PROC p.Asp170Tyr (c.508G>T) pathogenic?

PROC p.Asp170Tyr (c.508G>T) is classified Likely pathogenic in PROC (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.1747); Very rare (popmax 6.45e-05%); Associated with Reduced protein C activity.

What condition is associated with PROC p.Asp170Tyr (c.508G>T)?

PROC p.Asp170Tyr (c.508G>T) is associated with Reduced protein C activity (ClinVar).

How common is PROC p.Asp170Tyr (c.508G>T) in the general population?

PROC p.Asp170Tyr (c.508G>T) is very rare (popmax 6.45e-05%) (gnomAD).

What do computational predictors say about PROC p.Asp170Tyr (c.508G>T)?

AlphaMissense predicts likely benign (score 0.1747) — an in-silico prediction, not a clinical call.

PROC p.Asp170Tyr

c.508G>T · rs2104954946 · VCV1684350

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.45e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Reduced protein C activity

Computational evidence

Protein change
AlphaMissense	0.1747	likely benign ⚠ discordant with ClinVar
REVEL	0.586	indeterminate
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	26.1	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 6.45e-05%

Overall 6.45e-05% 1/1,550,586 alleles · very rare exomes 1/1,398,226 · genomes 0/152,360 · joint denominator

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.Asp170Tyr
Coding: c.508G>T
MANE Select: NM_000312
dbSNP: rs2104954946
Type: single nucleotide variant
Location: chr2:127423381 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 170: the egf-like 2 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

Similar variants

PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same condition
PROC p.Cys147Tyr Likely pathogenic ★★ same condition
PROC c.797-2A>T Likely pathogenic ★ same condition
PROC p.Ser141Pro Likely pathogenic ★ same condition
PROC p.Thr340Lys Likely pathogenic ★ same condition
PROC p.Trp444Ter Likely pathogenic ★ same condition
PROC p.Val26Met Likely pathogenic ★ ⚠ same condition
PROC p.Ala388Val Conflicting classifications of pathogenicity ★ ⚠ 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-asp170tyr (accessed [today's date]).

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