Is REL p.Arg389Cys (c.1165C>T) pathogenic?

REL p.Arg389Cys (c.1165C>T) is classified Conflicting classifications of pathogenicity in REL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-08). AlphaMissense: likely benign (0.0875); Very rare (popmax 0.00329%, sas).

How common is REL p.Arg389Cys (c.1165C>T) in the general population?

REL p.Arg389Cys (c.1165C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about REL p.Arg389Cys (c.1165C>T)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

REL p.Arg389Cys

c.1165C>T · rs772899527 · VCV2217016

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.60	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 0.63	GERP 0.35
Regional constraint	o/e 1.00	unconstrained · MANE · 1,945 bp · p 0.96 · regional, not allelic
Overall
CADD	17.46	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R421C vs ClinVar R389C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,086 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00229% 37/1,614,020 alleles · very rare exomes 29/1,461,868 · genomes 8/152,152 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00625%	16,005
South Asiangrpmax	0.00329%	30,362
Remaining individualsnot grpmax-eligible	0.0032%	31,242
East Asian	0.00223%	44,890
European (non-Finnish)	0.0022%	45,386
African / African-American	0.00133%	74,910

Finnish 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: REL
Protein: p.Arg389Cys
Coding: c.1165C>T
MANE Select: NM_001291746
dbSNP: rs772899527
Type: single nucleotide variant
Location: chr2:60921936 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.46
Residue 421 UniProt numbering: the 'disordered' region

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

Similar variants

REL p.Arg389= Likely benign ★ same residue
REL p.Asp224Asn Uncertain significance ★★ ⚠ same type
REL p.Gln503His Uncertain significance ★★ ⚠ same type
REL p.Leu298Val Uncertain significance ★★ ⚠ same type
REL p.Met372Lys Uncertain significance ★★ ⚠ same type
REL p.Met372Val Uncertain significance ★★ ⚠ same type
REL p.Phe559Leu Uncertain significance ★★ ⚠ same type
REL p.Ser556Gly 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/rel-p-arg389cys (accessed [today's date]).

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