Is RIN2 p.Val68Leu (c.202G>T) pathogenic?

RIN2 p.Val68Leu (c.202G>T) is classified Uncertain significance in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0869); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Val68Leu (c.202G>T)?

RIN2 p.Val68Leu (c.202G>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Val68Leu (c.202G>T) in the general population?

RIN2 p.Val68Leu (c.202G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about RIN2 p.Val68Leu (c.202G>T)?

AlphaMissense predicts likely benign (score 0.0869) — an in-silico prediction, not a clinical call.

RIN2 p.Val68Leu

c.202G>T · VCV4629178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0869 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0869	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.18	GERP -4
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	9.231	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 0.00134% African / African-American · 1/74,888 alleles

Overall 0.000186% 3/1,613,296 alleles · very rare exomes 2/1,461,148 · genomes 1/152,148 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,454
African / African-Americangrpmax	0.00134%	74,888
European (non-Finnish)	8.48e-05%	1,179,720

Remaining individuals 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: RIN2
Protein: p.Val68Leu
Coding: c.202G>T
MANE Select: NM_018993
Type: single nucleotide variant
Location: chr20:19956658 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30

Full RIN2 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

RASSF4 p.Arg68Gln Uncertain significance ★ ⚠ same residue
RASSF4 p.Arg68Trp Uncertain significance ★ ⚠ same residue
RIN2 p.Val68Met Uncertain significance ★ ⚠ same residue
RIN2 p.Ala205Val Uncertain significance ★★ ⚠ same condition
RIN2 p.Ala72Thr Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg135Cys Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg170Trp Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg255Thr Uncertain significance ★★ ⚠ same condition

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/rin2-p-val68leu (accessed [today's date]).

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