Is RELA p.Val165Ala (c.494T>C) pathogenic?

RELA p.Val165Ala (c.494T>C) is classified Uncertain significance in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-06). AlphaMissense: likely pathogenic (0.8177); Very rare (popmax 0.000593%, nfe).

How common is RELA p.Val165Ala (c.494T>C) in the general population?

RELA p.Val165Ala (c.494T>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about RELA p.Val165Ala (c.494T>C)?

AlphaMissense predicts likely pathogenic (score 0.8177) — an in-silico prediction, not a clinical call.

RELA p.Val165Ala

c.494T>C · rs957917859 · VCV1388089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8177 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8177	likely pathogenic
REVEL	0.285	benign-leaning
SaProt	LLR -8.74	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP -0.48, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 3,429 bp · p 2.3e-11 · regional, not allelic
Overall
CADD	25.0	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 0.000593% European (non-Finnish) · 7/1,179,990 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,764 alleles · very rare exomes 5/1,461,650 · genomes 2/152,114 · 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: RELA
Protein: p.Val165Ala
Coding: c.494T>C
MANE Select: NM_021975
dbSNP: rs957917859
Type: single nucleotide variant
Location: chr11:65659731 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.52 · 88 PDB
Residue 165: the rhd domain; a β-strand

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

Similar variants

RELA p.Val165= Benign ★ same residue
RELA p.Arg198Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Arg236Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Arg329Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Gln372Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Ala264Val Uncertain significance ★★ ⚠ same type
RELA p.Ala404Pro Uncertain significance ★★ ⚠ same type
RELA p.Ala404Thr 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/rela-p-val165ala (accessed [today's date]).

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