Is PGC p.Phe26Leu (c.78T>G) pathogenic?

PGC p.Phe26Leu (c.78T>G) is classified Uncertain significance in PGC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-25). AlphaMissense: likely pathogenic (0.609); Very rare (popmax 0.00267%, afr).

How common is PGC p.Phe26Leu (c.78T>G) in the general population?

PGC p.Phe26Leu (c.78T>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PGC p.Phe26Leu (c.78T>G)?

AlphaMissense predicts likely pathogenic (score 0.609) — an in-silico prediction, not a clinical call.

PGC p.Phe26Leu

c.78T>G · VCV3931204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.609	likely pathogenic
REVEL	0.056	moderately benign-leaning
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.1	GERP -9.4
Regional constraint	o/e 0.97	unconstrained · MANE · 10 kb · p 0.46 · regional, not allelic
Overall
CADD	0.131	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 0.00267% African / African-American · 2/74,904 alleles

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

Overall 0.000124% 2/1,613,884 alleles · very rare exomes 0/1,461,766 · genomes 2/152,118 · 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: PGC
Protein: p.Phe26Leu
Coding: c.78T>G
MANE Select: NM_002630
Type: single nucleotide variant
Location: chr6:41744790 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.60 · 2 PDB
Residue 26: 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-phe26leu (accessed [today's date]).

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