Is PGD p.Met361Ile (c.1083G>A) pathogenic?

PGD p.Met361Ile (c.1083G>A) is classified Uncertain significance in PGD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely pathogenic (0.8832); Ultra-rare (popmax 0.0356%, eas).

How common is PGD p.Met361Ile (c.1083G>A) in the general population?

PGD p.Met361Ile (c.1083G>A) is ultra-rare (popmax 0.0356%, eas) (gnomAD).

What do computational predictors say about PGD p.Met361Ile (c.1083G>A)?

AlphaMissense predicts likely pathogenic (score 0.8832) — an in-silico prediction, not a clinical call.

PGD p.Met361Ile

c.1083G>A · rs759755207 · VCV2377152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8832 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8832	likely pathogenic
REVEL	0.412	indeterminate
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 20 kb · p 1e-07 · regional, not allelic
Overall
CADD	25.3	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 0.0356% East Asian · 16/44,894 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00186% 30/1,613,332 alleles · ultra-rare exomes 27/1,461,156 · genomes 3/152,176 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0356%	2,806
South Asian	0.0088%	11,370
Remaining individualsnot grpmax-eligible	0.0048%	20,821
Finnishnot grpmax-eligible	0.00469%	21,339

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: PGD
Protein: p.Met361Ile
Coding: c.1083G>A
MANE Select: NM_002631
dbSNP: rs759755207
Type: single nucleotide variant
Location: chr1:10417483 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 96.98 · 4 PDB
Residue 361: an α-helix

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

Similar variants

PGD c.519+2C>T Uncertain significance ★ same type
PGD p.Ala149Gly Uncertain significance ★ ⚠ same type
PGD p.Ala258Val Uncertain significance ★ ⚠ same type
PGD p.Ala336Pro Uncertain significance ★ ⚠ same type
PGD p.Ala345Gly Uncertain significance ★ ⚠ same type
PGD p.Arg407Gln Uncertain significance ★ ⚠ same type
PGD p.Asn354Ser Uncertain significance ★ ⚠ same type
PGD p.Asn354Tyr 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/pgd-p-met361ile (accessed [today's date]).

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