Is RS1 p.Pro86Leu (c.257C>T) pathogenic?

RS1 p.Pro86Leu (c.257C>T) is classified Uncertain significance in RS1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-06-25). AlphaMissense: likely benign (0.0796); Very rare (popmax 0.00353%, sas); Associated with X-linked retinoschisis.

What condition is associated with RS1 p.Pro86Leu (c.257C>T)?

RS1 p.Pro86Leu (c.257C>T) is associated with X-linked retinoschisis (ClinVar).

How common is RS1 p.Pro86Leu (c.257C>T) in the general population?

RS1 p.Pro86Leu (c.257C>T) is very rare (popmax 0.00353%, sas) (gnomAD).

What do computational predictors say about RS1 p.Pro86Leu (c.257C>T)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

RS1 p.Pro86Leu

c.257C>T · rs761385911 · VCV971861

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00353%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

X-linked retinoschisis

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.4	GERP -2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 30 kb · p 0.0049 · regional, not allelic
Overall
CADD	17.65	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 0.00353% South Asian · 2/56,691 alleles

Filtering AF 0.000585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000911% 11/1,207,111 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00646%	15,491
South Asiangrpmax	0.00353%	28,345
Admixed American	0.0022%	45,558
European (non-Finnish)	0.00056%	178,696

Finnish 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: RS1
Protein: p.Pro86Leu
Coding: c.257C>T
MANE Select: NM_001323289 · reported on NM_000330
dbSNP: rs761385911
Type: single nucleotide variant
Location: chrX:18647260 (GRCh38)

Full RS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked retinoschisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/rs1-p-pro86leu (accessed [today's date]).

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