Is RCC2 p.Val83Ala (c.248T>C) pathogenic?

RCC2 p.Val83Ala (c.248T>C) is classified Uncertain significance in RCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1688); Rare (popmax 0.883%, sas).

How common is RCC2 p.Val83Ala (c.248T>C) in the general population?

RCC2 p.Val83Ala (c.248T>C) is rare (popmax 0.883%, sas) (gnomAD).

What do computational predictors say about RCC2 p.Val83Ala (c.248T>C)?

AlphaMissense predicts likely benign (score 0.1688) — an in-silico prediction, not a clinical call.

RCC2 p.Val83Ala

c.248T>C · VCV4152080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1688 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.883%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1688	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -4.67	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 3.4	GERP 0.061, phastCons 0.99
Regional constraint	o/e 1.23	unconstrained · MANE · 9,337 bp · p 0.0036 · regional, not allelic
Overall
CADD	16.74	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.883% South Asian · 523/59,204 alleles

Filtering AF 0.821% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.796%

Overall 0.277% 3,637/1,313,788 alleles · rare exomes 3,293/1,166,292 · genomes 344/147,496 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.883%	113
Middle Eastern	0.467%	214
Finnishnot grpmax-eligible	0.33%	303
European (non-Finnish)	0.276%	363
Remaining individualsnot grpmax-eligible	0.197%	507
Admixed American	0.0725%	1,379
African / African-American	0.0518%	1,932
East Asian	0.00411%	24,308

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: RCC2
Protein: p.Val83Ala
Coding: c.248T>C
MANE Select: NM_018715
Type: single nucleotide variant
Location: chr1:17438267 (GRCh38)
Gene constraint: LOEUF 0.508 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 88.97 · 1 PDB
Residue 83: the 'disordered' region

Full RCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RCC2 p.Ala146Glu Uncertain significance ★ ⚠ same type
RCC2 p.Ala490Thr Uncertain significance ★ ⚠ same type
RCC2 p.Ala6Val Uncertain significance ★ ⚠ same type
RCC2 p.Ala78Thr Uncertain significance ★ ⚠ same type
RCC2 p.Ala7Gly Uncertain significance ★ ⚠ same type
RCC2 p.Ala9Thr Uncertain significance ★ ⚠ same type
RCC2 p.Arg149Gln Uncertain significance ★ ⚠ same type
RCC2 p.Arg151Trp 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/rcc2-p-val83ala (accessed [today's date]).

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