Is SYNCRIP p.Trp622Arg (c.1864T>C) pathogenic?

SYNCRIP p.Trp622Arg (c.1864T>C) is classified Uncertain significance in SYNCRIP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-11). AlphaMissense: likely pathogenic (0.9957); Very rare (popmax 8.55e-05%, nfe); Associated with SYNCRIP-related disorder.

What condition is associated with SYNCRIP p.Trp622Arg (c.1864T>C)?

SYNCRIP p.Trp622Arg (c.1864T>C) is associated with SYNCRIP-related disorder (ClinVar).

How common is SYNCRIP p.Trp622Arg (c.1864T>C) in the general population?

SYNCRIP p.Trp622Arg (c.1864T>C) is very rare (popmax 8.55e-05%, nfe) (gnomAD).

What do computational predictors say about SYNCRIP p.Trp622Arg (c.1864T>C)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

SYNCRIP p.Trp622Arg

c.1864T>C · rs2537715397 · VCV2631938

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.55e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

SYNCRIP-related disorder

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic
REVEL	0.528	indeterminate
SaProt	LLR -5.43	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 325 bp · p 0.12 · regional, not allelic
Overall
CADD	31.0	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 8.55e-05% European (non-Finnish) · 1/1,170,234 alleles

Overall 6.28e-05% 1/1,591,828 alleles · very rare exomes 1/1,439,720 · genomes 0/152,108 · joint denominator

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: SYNCRIP
Protein: p.Trp622Arg
Coding: c.1864T>C
MANE Select: NM_006372
dbSNP: rs2537715397
Type: single nucleotide variant
Location: chr6:85614764 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.83 · 4 PDB
Residue 622: the 'disordered' region

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

Disease context

SYNCRIP-related disorder

Similar variants

SYNCRIP p.Ala521Thr Uncertain significance ★ ⚠ same condition
SYNCRIP p.Val561Gly Uncertain significance ★ ⚠ same condition
SYNCRIP p.Thr101Ile Uncertain significance ⚠ same condition
SYNCRIP p.Tyr523His Uncertain significance ⚠ same condition
SYNCRIP p.Arg548= Likely benign same condition
SYNCRIP p.Gln592= Likely benign same condition
SYNCRIP p.Gln596= Likely benign same condition
SYNCRIP p.Pro147fs Likely pathogenic ★ 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/syncrip-p-trp622arg (accessed [today's date]).

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