Is PGC p.Leu368Phe (c.1102C>T) pathogenic?

PGC p.Leu368Phe (c.1102C>T) is classified Uncertain significance in PGC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). AlphaMissense: likely pathogenic (0.902); Ultra-rare (popmax 0.0607%, nfe).

How common is PGC p.Leu368Phe (c.1102C>T) in the general population?

PGC p.Leu368Phe (c.1102C>T) is ultra-rare (popmax 0.0607%, nfe) (gnomAD).

What do computational predictors say about PGC p.Leu368Phe (c.1102C>T)?

AlphaMissense predicts likely pathogenic (score 0.902) — an in-silico prediction, not a clinical call.

PGC p.Leu368Phe

c.1102C>T · rs144119548 · VCV2345941

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.902 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0607%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.902	likely pathogenic
REVEL	0.668	pathogenic-leaning
SaProt	LLR -7.30	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 4.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 10 kb · p 0.46 · regional, not allelic
Overall
CADD	25.4	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 0.0607% European (non-Finnish) · 716/1,180,008 alleles

Filtering AF 0.0569% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0555%

Overall 0.0521% 841/1,614,128 alleles · ultra-rare exomes 793/1,461,852 · genomes 48/152,276 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0718%	1,392
European (non-Finnish)grpmax	0.0607%	1,648
Remaining individualsnot grpmax-eligible	0.0528%	1,894
South Asian	0.0373%	2,679
Admixed American	0.015%	6,668
African / African-American	0.004%	25,010

Finnish 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: PGC
Protein: p.Leu368Phe
Coding: c.1102C>T
MANE Select: NM_002630
dbSNP: rs144119548
Type: single nucleotide variant
Location: chr6:41736917 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 2 PDB
Residue 368: the peptidase a1 domain; an α-helix

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

Similar variants

PGC p.Ala174Val Uncertain significance ★ ⚠ same type
PGC p.Ala183Thr Uncertain significance ★ ⚠ same type
PGC p.Ala186Val Uncertain significance ★ ⚠ same type
PGC p.Ala224Pro Uncertain significance ★ ⚠ same type
PGC p.Ala242Val Uncertain significance ★ ⚠ same type
PGC p.Ala388Thr Uncertain significance ★ ⚠ same type
PGC p.Ala67Gly Uncertain significance ★ ⚠ same type
PGC p.Ala67Val Uncertain significance ★ ⚠ 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/pgc-p-leu368phe (accessed [today's date]).

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