Is REL p.Ala180Val (c.539C>T) pathogenic?

REL p.Ala180Val (c.539C>T) is classified Uncertain significance in REL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely pathogenic (0.988); Very rare (popmax 0.000173%, nfe).

How common is REL p.Ala180Val (c.539C>T) in the general population?

REL p.Ala180Val (c.539C>T) is very rare (popmax 0.000173%, nfe) (gnomAD).

What do computational predictors say about REL p.Ala180Val (c.539C>T)?

AlphaMissense predicts likely pathogenic (score 0.988) — an in-silico prediction, not a clinical call.

REL p.Ala180Val

c.539C>T · rs764825785 · VCV2111844

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000173%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.988	likely pathogenic
REVEL	0.569	indeterminate
SaProt	LLR -11.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	28.9	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 0.000173% European (non-Finnish) · 2/1,156,672 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000127% 2/1,578,258 alleles · very rare exomes 2/1,426,088 · genomes 0/152,170 · 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.Ala180Val
Coding: c.539C>T
MANE Select: NM_001291746
dbSNP: rs764825785
Type: single nucleotide variant
Location: chr2:60918194 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.46
Residue 180: the rhd domain

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

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REL p.Met372Val Uncertain significance ★★ ⚠ same type
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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-ala180val (accessed [today's date]).

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