Is REL p.Pro256Ser (c.766C>T) pathogenic?

REL p.Pro256Ser (c.766C>T) is classified Uncertain significance in REL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: ambiguous (0.5037); Ultra-rare (popmax 0.0533%, amr).

How common is REL p.Pro256Ser (c.766C>T) in the general population?

REL p.Pro256Ser (c.766C>T) is ultra-rare (popmax 0.0533%, amr) (gnomAD).

What do computational predictors say about REL p.Pro256Ser (c.766C>T)?

AlphaMissense predicts ambiguous (score 0.5037) — an in-silico prediction, not a clinical call.

REL p.Pro256Ser

c.766C>T · rs747391156 · VCV2372590

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5037 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5037	ambiguous
REVEL	0.143	moderately benign-leaning
SaProt	LLR -9.66	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 29 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	19.77	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 0.0533% Admixed American · 32/59,990 alleles

Filtering AF 0.0388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.00198% 32/1,613,938 alleles · ultra-rare exomes 31/1,461,824 · genomes 1/152,114 · 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: REL
Protein: p.Pro256Ser
Coding: c.766C>T
MANE Select: NM_001291746
dbSNP: rs747391156
Type: single nucleotide variant
Location: chr2:60918519 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.46
Residue 256: the rhd domain

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

Similar variants

REL p.Pro256His Uncertain significance ★ ⚠ same residue
REL p.Pro256= 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

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-pro256ser (accessed [today's date]).

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