Is PGC p.Ala174Val (c.521C>T) pathogenic?

PGC p.Ala174Val (c.521C>T) is classified Uncertain significance in PGC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: ambiguous (0.5146); Ultra-rare (popmax 0.0164%, mid).

How common is PGC p.Ala174Val (c.521C>T) in the general population?

PGC p.Ala174Val (c.521C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PGC p.Ala174Val (c.521C>T)?

AlphaMissense predicts ambiguous (score 0.5146) — an in-silico prediction, not a clinical call.

PGC p.Ala174Val

c.521C>T · rs764935633 · VCV2603564

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5146	ambiguous
REVEL	0.267	benign-leaning
SaProt	LLR -11.17	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 2.6, phastCons 0.55
Regional constraint	o/e 0.97	unconstrained · MANE · 10 kb · p 0.46 · regional, not allelic
Overall
CADD	18.26	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00192% 31/1,613,978 alleles · ultra-rare exomes 27/1,461,834 · genomes 4/152,144 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.00333%	30,004
South Asian	0.00329%	30,360
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00195%	51,304

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.Ala174Val
Coding: c.521C>T
MANE Select: NM_002630
dbSNP: rs764935633
Type: single nucleotide variant
Location: chr6:41742416 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 2 PDB
Residue 174: the peptidase a1 domain

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

Similar variants

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
PGC p.Arg114Cys 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-ala174val (accessed [today's date]).

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