Is PAM p.Pro64Ala (c.190C>G) pathogenic?

PAM p.Pro64Ala (c.190C>G) is classified Uncertain significance in PAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.4134); Very rare (popmax 0.00667%, amr).

How common is PAM p.Pro64Ala (c.190C>G) in the general population?

PAM p.Pro64Ala (c.190C>G) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about PAM p.Pro64Ala (c.190C>G)?

AlphaMissense predicts ambiguous (score 0.4134) — an in-silico prediction, not a clinical call.

PAM p.Pro64Ala

c.190C>G · VCV4564284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Computational evidence

Protein change
AlphaMissense	0.4134	ambiguous
REVEL	0.501	indeterminate
SaProt	LLR -10.82	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 137 kb · p 0.44 · regional, not allelic
Overall
CADD	26.3	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 0.00667% Admixed American · 4/59,948 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000311% 5/1,608,744 alleles · very rare exomes 4/1,456,676 · genomes 1/152,068 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,987
European (non-Finnish)	8.51e-05%	1,175,562

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: PAM
Protein: p.Pro64Ala
Coding: c.190C>G
MANE Select: NM_001177306
Type: single nucleotide variant
Location: chr5:102867373 (GRCh38)
Gene constraint: LOEUF 0.863 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.54
Residue 64: the 'peptidylglycine alpha-hydroxylating monooxygenase' region

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

Similar variants

PAM p.Phe31Tyr Benign/Likely benign ★★ same type
PAM p.Ala58Thr Uncertain significance ★ ⚠ same type
PAM p.Ala787Gly Uncertain significance ★ ⚠ same type
PAM p.Ala787Val Uncertain significance ★ ⚠ same type
PAM p.Arg175Thr Uncertain significance ★ ⚠ same type
PAM p.Arg776His Uncertain significance ★ ⚠ same type
PAM p.Arg80Gln Uncertain significance ★ ⚠ same type
PAM p.Arg888Gln 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/pam-p-pro64ala (accessed [today's date]).

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