Is PROC p.Thr110Met (c.329C>T) pathogenic?

PROC p.Thr110Met (c.329C>T) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-06). AlphaMissense: likely benign (0.092); Very rare (popmax 0.00267%, afr).

How common is PROC p.Thr110Met (c.329C>T) in the general population?

PROC p.Thr110Met (c.329C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PROC p.Thr110Met (c.329C>T)?

AlphaMissense predicts likely benign (score 0.092) — an in-silico prediction, not a clinical call.

PROC p.Thr110Met

c.329C>T · rs370147557 · VCV3253048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.092	likely benign
REVEL	0.472	indeterminate
SaProt	LLR -9.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.9
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	13.23	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00267% African / African-American · 2/74,846 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000373% 6/1,609,808 alleles · very rare exomes 4/1,457,454 · genomes 2/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,423
Remaining individualsnot grpmax-eligible	0.00161%	62,254
European (non-Finnish)	0.000255%	392,759

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.Thr110Met
Coding: c.329C>T
MANE Select: NM_000312
dbSNP: rs370147557
Type: single nucleotide variant
Location: chr2:127423100 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 110: a β-strand; the egf-like 1 domain

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

Similar variants

PROC p.Thr110Arg Uncertain significance ★★ ⚠ same residue
PROC p.Ala178Pro Likely pathogenic ★★ ⚠ same type
PROC p.Ala309Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg199Ter Pathogenic ★★ same type
PROC p.Arg211Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg211Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg220Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
PROC p.Arg220Trp 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/proc-p-thr110met (accessed [today's date]).

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