Is REL p.Pro256His (c.767C>A) pathogenic?

REL p.Pro256His (c.767C>A) is classified Uncertain significance in REL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-20). AlphaMissense: likely pathogenic (0.8496); Ultra-rare (popmax 0.015%, amr).

How common is REL p.Pro256His (c.767C>A) in the general population?

REL p.Pro256His (c.767C>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about REL p.Pro256His (c.767C>A)?

AlphaMissense predicts likely pathogenic (score 0.8496) — an in-silico prediction, not a clinical call.

REL p.Pro256His

c.767C>A · rs367805383 · VCV2176381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8496 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8496	likely pathogenic
REVEL	0.347	indeterminate
SaProt	LLR -12.45	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 29 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	25.3	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 0.015% Admixed American · 9/59,978 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.0018% 29/1,613,928 alleles · ultra-rare exomes 24/1,461,832 · genomes 5/152,096 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,664
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.00153%	65,556
African / African-American	0.00134%	74,888

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.Pro256His
Coding: c.767C>A
MANE Select: NM_001291746
dbSNP: rs367805383
Type: single nucleotide variant
Location: chr2:60918520 (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.Pro256Ser 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-pro256his (accessed [today's date]).

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