Is PUS7 p.Met321Val (c.961A>G) pathogenic?

PUS7 p.Met321Val (c.961A>G) is classified Uncertain significance in PUS7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.1355); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with PUS7 p.Met321Val (c.961A>G)?

PUS7 p.Met321Val (c.961A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PUS7 p.Met321Val (c.961A>G) in the general population?

PUS7 p.Met321Val (c.961A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PUS7 p.Met321Val (c.961A>G)?

AlphaMissense predicts likely benign (score 0.1355) — an in-silico prediction, not a clinical call.

PUS7 p.Met321Val

c.961A>G · VCV4628678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1355 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1355	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -4.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.1	GERP 6.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 51 kb · p 0.015 · regional, not allelic
Overall
CADD	21.2	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 0.0165% Middle Eastern · 1/6,044 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000373% 6/1,609,108 alleles · ultra-rare exomes 4/1,459,238 · genomes 2/149,870 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,044
South Asian	0.0033%	30,325
Admixed American	0.00168%	59,686
Remaining individualsnot grpmax-eligible	0.0016%	62,360

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: PUS7
Protein: p.Met321Val
Coding: c.961A>G
MANE Select: NM_019042
Type: single nucleotide variant
Location: chr7:105482400 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.67 · 1 PDB
Residue 321: a β-strand

Full PUS7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PUS7 p.Met321Ile Uncertain significance ★ ⚠ same residue
PUS7 p.Met321Thr Uncertain significance ★ ⚠ same residue
PUS7 p.Arg661His Uncertain significance ★★ ⚠ same condition
PUS7 p.Met104Val Uncertain significance ★★ ⚠ same condition
PUS7 p.Glu180Lys Likely benign ★★ same condition
PUS7 c.398+1G>T Conflicting classifications of pathogenicity ★ same condition
PUS7 p.Ala236Thr Uncertain significance ★ ⚠ same condition
PUS7 p.Ala314Ser Uncertain significance ★ ⚠ same condition

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/pus7-p-met321val (accessed [today's date]).

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