Is SYNCRIP p.Arg548Cys (c.1642C>T) pathogenic?

SYNCRIP p.Arg548Cys (c.1642C>T) is classified Uncertain significance in SYNCRIP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-25). AlphaMissense: likely pathogenic (0.7901); Very rare (popmax 0.00167%, amr).

How common is SYNCRIP p.Arg548Cys (c.1642C>T) in the general population?

SYNCRIP p.Arg548Cys (c.1642C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SYNCRIP p.Arg548Cys (c.1642C>T)?

AlphaMissense predicts likely pathogenic (score 0.7901) — an in-silico prediction, not a clinical call.

SYNCRIP p.Arg548Cys

c.1642C>T · rs1455212560 · VCV2178199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7901 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7901	likely pathogenic
REVEL	0.296	indeterminate
SaProt	LLR -12.95	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 325 bp · p 0.12 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/59,938 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000372% 6/1,613,234 alleles · very rare exomes 3/1,461,256 · genomes 3/151,978 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,538
Admixed Americangrpmax	0.00167%	59,938
African / African-American	0.00134%	74,836
European (non-Finnish)	0.000254%	393,201

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg548Cys
Coding: c.1642C>T
MANE Select: NM_006372
dbSNP: rs1455212560
Type: single nucleotide variant
Location: chr6:85614986 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.83 · 4 PDB
Residue 548: the 'interaction with apobec1' region; the '8 x 3 aa repeats of r-g-g' region; the 'disordered' region; the 'interaction with smn' region

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

Similar variants

SYNCRIP p.Arg548= Likely benign same residue
SYNCRIP p.Ala216Thr Uncertain significance ★★ same type
SYNCRIP p.Asn243Ser Uncertain significance ★★ ⚠ same type
SYNCRIP p.Pro440Leu Uncertain significance ★★ ⚠ same type
SYNCRIP p.Pro508Leu Uncertain significance ★★ ⚠ same type
SYNCRIP p.Ser116Gly Uncertain significance ★★ ⚠ same type
SYNCRIP p.Glu612Val Likely benign ★★ ⚠ same type
SYNCRIP p.Arg446Ter Pathogenic ★ 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/syncrip-p-arg548cys (accessed [today's date]).

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