Is SYNJ2 p.Met332Val (c.994A>G) pathogenic?

SYNJ2 p.Met332Val (c.994A>G) is classified Uncertain significance in SYNJ2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.2317); Ultra-rare (popmax 0.0165%, mid).

How common is SYNJ2 p.Met332Val (c.994A>G) in the general population?

SYNJ2 p.Met332Val (c.994A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SYNJ2 p.Met332Val (c.994A>G)?

AlphaMissense predicts likely benign (score 0.2317) — an in-silico prediction, not a clinical call.

SYNJ2 p.Met332Val

c.994A>G · rs745741351 · VCV3172832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2317 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2317	likely benign
REVEL	0.387	indeterminate
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 114 kb · p 0.16 · regional, not allelic
Overall
CADD	24.9	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 · 1/6,074 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00248% 40/1,614,008 alleles · ultra-rare exomes 36/1,461,802 · genomes 4/152,206 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)	0.0028%	35,759
Admixed American	0.00167%	60,008
South Asian	0.0011%	91,092

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: SYNJ2
Protein: p.Met332Val
Coding: c.994A>G
MANE Select: NM_003898
dbSNP: rs745741351
Type: single nucleotide variant
Location: chr6:158062031 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.47 · 1 PDB
Residue 332: the sac domain

Full SYNJ2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SYNJ2 p.Asp1071Glu Uncertain significance ★★ ⚠ same type
SYNJ2 p.Val420Ala Likely benign ★★ same type
SYNJ2 p.Ala1072Thr Uncertain significance ★ ⚠ same type
SYNJ2 p.Ala111Asp Uncertain significance ★ ⚠ same type
SYNJ2 p.Ala1186Thr Uncertain significance ★ ⚠ same type
SYNJ2 p.Ala1199Thr Uncertain significance ★ ⚠ same type
SYNJ2 p.Ala1274Gly Uncertain significance ★ ⚠ same type
SYNJ2 p.Ala1298Ser 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/synj2-p-met332val (accessed [today's date]).

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