Is ME3 p.Arg321Gln (c.962G>A) pathogenic?

ME3 p.Arg321Gln (c.962G>A) is classified Uncertain significance in ME3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.1669); Very rare (popmax 0.0033%, sas).

How common is ME3 p.Arg321Gln (c.962G>A) in the general population?

ME3 p.Arg321Gln (c.962G>A) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about ME3 p.Arg321Gln (c.962G>A)?

AlphaMissense predicts likely benign (score 0.1669) — an in-silico prediction, not a clinical call.

ME3 p.Arg321Gln

c.962G>A · rs770484153 · VCV2211250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1669	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -9.86	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 231 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	29.3	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 0.0033% South Asian · 3/91,044 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00103% 15/1,461,764 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,348
Remaining individualsnot grpmax-eligible	0.0032%	31,251
Admixed American	0.00167%	60,028
European (non-Finnish)	0.000763%	131,113

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: ME3
Protein: p.Arg321Gln
Coding: c.962G>A
MANE Select: NM_001161586
dbSNP: rs770484153
Type: single nucleotide variant
Location: chr11:86450356 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.20 · 7 PDB
Residue 321: an α-helix

Full ME3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ME3 p.Ala21Thr Uncertain significance ★ ⚠ same type
ME3 p.Ala29Glu Uncertain significance ★ ⚠ same type
ME3 p.Ala420Asp Uncertain significance ★ ⚠ same type
ME3 p.Arg10Trp Uncertain significance ★ ⚠ same type
ME3 p.Arg190Cys Uncertain significance ★ ⚠ same type
ME3 p.Arg24Pro Uncertain significance ★ ⚠ same type
ME3 p.Arg289His Uncertain significance ★ ⚠ same type
ME3 p.Arg404Met 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/me3-p-arg321gln (accessed [today's date]).

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