Is REL p.Tyr355Ser (c.1064A>C) pathogenic?

REL p.Tyr355Ser (c.1064A>C) is classified Uncertain significance in REL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). AlphaMissense: likely benign (0.105); Very rare (popmax 0.00668%, eas).

How common is REL p.Tyr355Ser (c.1064A>C) in the general population?

REL p.Tyr355Ser (c.1064A>C) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about REL p.Tyr355Ser (c.1064A>C)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

REL p.Tyr355Ser

c.1064A>C · rs373394733 · VCV2181454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -4.73	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 6.1	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 1,945 bp · p 0.96 · regional, not allelic
Overall
CADD	18.31	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Y387S vs ClinVar Y355S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,880 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00041% 6/1,461,826 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,960
Remaining individualsnot grpmax-eligible	0.0032%	31,256
European (non-Finnish)	8.47e-05%	1,179,981

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.Tyr355Ser
Coding: c.1064A>C
MANE Select: NM_001291746
dbSNP: rs373394733
Type: single nucleotide variant
Location: chr2:60921835 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.46

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

Similar variants

REL p.Tyr355= 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-tyr355ser (accessed [today's date]).

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