Is RALA p.Lys166Arg (c.497A>G) pathogenic?

RALA p.Lys166Arg (c.497A>G) is classified Conflicting classifications of pathogenicity in RALA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-19). AlphaMissense: likely benign (0.1485); Very rare (popmax 8.49e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RALA p.Lys166Arg (c.497A>G)?

RALA p.Lys166Arg (c.497A>G) is associated with Inborn genetic diseases (ClinVar).

How common is RALA p.Lys166Arg (c.497A>G) in the general population?

RALA p.Lys166Arg (c.497A>G) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about RALA p.Lys166Arg (c.497A>G)?

AlphaMissense predicts likely benign (score 0.1485) — an in-silico prediction, not a clinical call.

RALA p.Lys166Arg

c.497A>G · rs954149915 · VCV2392763

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1485	likely benign
REVEL	0.547	indeterminate
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.40	donor gain · deltas
Pangolin	Δ0.55	gain · loss 0.54 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 20 kb · p 4.8e-21 · regional, not allelic
Overall
CADD	33.0	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 8.49e-05% European (non-Finnish) · 1/1,178,374 alleles

Overall 6.21e-05% 1/1,609,170 alleles · very rare exomes 1/1,456,810 · genomes 0/152,360 · 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: RALA
Protein: p.Lys166Arg
Coding: c.497A>G
MANE Select: NM_005402
dbSNP: rs954149915
Type: single nucleotide variant
Location: chr7:39696858 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 89.54 · 17 PDB
Residue 166: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RALA p.Thr156Ile Likely pathogenic ★★ same type
RALA p.Val25Met Pathogenic/Likely pathogenic ★★ same type
RALA p.Ala196Thr Uncertain significance ★★ ⚠ same type
RALA p.Arg161Ter Uncertain significance ★★ same type
RALA p.Arg176Ter Uncertain significance ★★ same type
RALA p.Asp37Asn Uncertain significance ★★ ⚠ same type
RALA p.Phe101Ser Uncertain significance ★★ ⚠ same type
RALA c.114+10A>T Benign/Likely benign ★★ 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/rala-p-lys166arg (accessed [today's date]).

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