Is RIN2 p.Pro116Leu (c.347C>T) pathogenic?

RIN2 p.Pro116Leu (c.347C>T) is classified Benign in RIN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.3141); Low-frequency (popmax 1.28%, afr).

How common is RIN2 p.Pro116Leu (c.347C>T) in the general population?

RIN2 p.Pro116Leu (c.347C>T) is low-frequency (popmax 1.28%, afr) (gnomAD).

What do computational predictors say about RIN2 p.Pro116Leu (c.347C>T)?

AlphaMissense predicts likely benign (score 0.3141) — an in-silico prediction, not a clinical call.

RIN2 p.Pro116Leu

c.347C>T · rs147968123 · VCV506800

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3141 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.28%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3141	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -9.12	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 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	31.0	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 1.28% African / African-American · 952/74,260 alleles

Filtering AF 1.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.19%

Overall 0.0942% 1,483/1,574,728 alleles · low-frequency exomes 893/1,422,446 · genomes 590/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.28%	78
Ashkenazi Jewishnot grpmax-eligible	0.591%	169
Middle Eastern	0.219%	456
Remaining individualsnot grpmax-eligible	0.153%	654
Admixed American	0.0704%	1,421
South Asian	0.0197%	5,083
European (non-Finnish)	0.0174%	5,760

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.Pro116Leu
Coding: c.347C>T
MANE Select: NM_018993
dbSNP: rs147968123
Type: single nucleotide variant
Location: chr20:19956803 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 116: the sh2 domain

Full RIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIN2 p.Pro116= Likely benign ★★ same residue
RIN2 p.Ala205Val Uncertain significance ★★ ⚠ same type
RIN2 p.Ala72Thr Uncertain significance ★★ ⚠ same type
RIN2 p.Ala8Thr Uncertain significance ★★ ⚠ same type
RIN2 p.Arg135Cys Uncertain significance ★★ ⚠ same type
RIN2 p.Arg170Trp Uncertain significance ★★ ⚠ same type
RIN2 p.Arg255Thr Uncertain significance ★★ ⚠ same type
RIN2 p.Arg290Leu 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/rin2-p-pro116leu (accessed [today's date]).

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