Is PGAP2 p.Met21Val (c.61A>G) pathogenic?

PGAP2 p.Met21Val (c.61A>G) is classified Uncertain significance in PGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.049); Ultra-rare (popmax 0.0242%, sas).

How common is PGAP2 p.Met21Val (c.61A>G) in the general population?

PGAP2 p.Met21Val (c.61A>G) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about PGAP2 p.Met21Val (c.61A>G)?

AlphaMissense predicts likely benign (score 0.049) — an in-silico prediction, not a clinical call.

PGAP2 p.Met21Val

c.61A>G · VCV3697084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.049 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.049	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -3.06	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.44	GERP -3.8, phastCons 0.001
Regional constraint	o/e 0.48	unconstrained · MANE · 161 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	1.215	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0242% South Asian · 22/91,078 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00155% 25/1,614,016 alleles · ultra-rare exomes 24/1,461,806 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,140
European (non-Finnish)	0.000254%	393,318

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: PGAP2
Protein: p.Met21Val
Coding: c.61A>G
MANE Select: NM_014489
Type: single nucleotide variant
Location: chr11:3811320 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.00

Full PGAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PGAP2 p.Ala127Val Likely pathogenic ★★ same type
PGAP2 p.Arg238Pro Pathogenic/Likely pathogenic ★★ ⚠ same type
PGAP2 p.Thr294Met Likely pathogenic ★★ same type
PGAP2 c.602-3C>T Uncertain significance ★★ same type
PGAP2 p.Ala187Thr Uncertain significance ★★ ⚠ same type
PGAP2 p.Ala33Thr Uncertain significance ★★ ⚠ same type
PGAP2 p.Arg238Cys Uncertain significance ★★ ⚠ same type
PGAP2 p.Asn205Lys 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/pgap2-p-met21val (accessed [today's date]).

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