Is REL p.Ser525Pro (c.1573T>C) pathogenic?

REL p.Ser525Pro (c.1573T>C) is classified Conflicting classifications of pathogenicity in REL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0715); Ultra-rare (popmax 0.0187%, nfe).

How common is REL p.Ser525Pro (c.1573T>C) in the general population?

REL p.Ser525Pro (c.1573T>C) is ultra-rare (popmax 0.0187%, nfe) (gnomAD).

What do computational predictors say about REL p.Ser525Pro (c.1573T>C)?

AlphaMissense predicts likely benign (score 0.0715) — an in-silico prediction, not a clinical call.

REL p.Ser525Pro

c.1573T>C · rs149627368 · VCV2064823

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0715 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0715	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -6.45	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 -0.083	GERP 1.4
Regional constraint	o/e 1.00	unconstrained · MANE · 1,945 bp · p 0.96 · regional, not allelic
Overall
CADD	11.55	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 S557P vs ClinVar S525P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% European (non-Finnish) · 221/1,180,024 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.019% 306/1,614,028 alleles · ultra-rare exomes 291/1,461,852 · genomes 15/152,176 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.196%	510
Remaining individualsnot grpmax-eligible	0.0336%	2,976
European (non-Finnish)grpmax	0.0187%	5,339
Middle Eastern	0.0164%	6,084
Admixed American	0.00333%	29,997
African / African-American	0.00267%	37,456
Finnishnot grpmax-eligible	0.00156%	64,034

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: REL
Protein: p.Ser525Pro
Coding: c.1573T>C
MANE Select: NM_001291746
dbSNP: rs149627368
Type: single nucleotide variant
Location: chr2:60922344 (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.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
REL p.Ser563Asn 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-ser525pro (accessed [today's date]).

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