Is PROC p.Phe181Leu (c.541T>C) pathogenic?

PROC p.Phe181Leu (c.541T>C) is classified Uncertain significance in PROC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: likely pathogenic (0.9267); Very rare (popmax 0.00508%, nfe).

How common is PROC p.Phe181Leu (c.541T>C) in the general population?

PROC p.Phe181Leu (c.541T>C) is very rare (popmax 0.00508%, nfe) (gnomAD).

What do computational predictors say about PROC p.Phe181Leu (c.541T>C)?

AlphaMissense predicts likely pathogenic (score 0.9267) — an in-silico prediction, not a clinical call.

PROC p.Phe181Leu

c.541T>C · rs199469470 · VCV1677377

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9267 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00508%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9267	likely pathogenic
REVEL	0.747	pathogenic-leaning
SaProt	LLR -5.35	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.3	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 9,000 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	23.6	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 0.00508% European (non-Finnish) · 60/1,180,012 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00372% 60/1,613,916 alleles · very rare exomes 58/1,461,734 · genomes 2/152,182 · 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.Phe181Leu
Coding: c.541T>C
MANE Select: NM_000312
dbSNP: rs199469470
Type: single nucleotide variant
Location: chr2:127426090 (GRCh38)
Gene constraint: LOEUF 0.894 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35 · 12 PDB
Residue 181: a β-strand; a UniProt-annotated variant site (in patients with proc deficiency)

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

Similar variants

PROC p.Phe181Val Pathogenic/Likely pathogenic ★★ ⚠ 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-phe181leu (accessed [today's date]).

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