Is CLRN3 p.Ser91Leu (c.272C>T) pathogenic?

CLRN3 p.Ser91Leu (c.272C>T) is classified Likely benign in CLRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.0561); Ultra-rare (popmax 0.0129%, nfe).

How common is CLRN3 p.Ser91Leu (c.272C>T) in the general population?

CLRN3 p.Ser91Leu (c.272C>T) is ultra-rare (popmax 0.0129%, nfe) (gnomAD).

What do computational predictors say about CLRN3 p.Ser91Leu (c.272C>T)?

AlphaMissense predicts likely benign (score 0.0561) — an in-silico prediction, not a clinical call.

CLRN3 p.Ser91Leu

c.272C>T · VCV4230170

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0561 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0129%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0561	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.89 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.6	GERP -4.6
Regional constraint	o/e 1.08	unconstrained · MANE · 15 kb · p 0.19 · regional, not allelic
Overall
CADD	0.026	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 0.0129% European (non-Finnish) · 152/1,180,030 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00991% 160/1,614,182 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0129%	7,763
Remaining individualsnot grpmax-eligible	0.0064%	15,628
Admixed American	0.00333%	30,012
African / African-American	0.00267%	37,520

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: CLRN3
Protein: p.Ser91Leu
Coding: c.272C>T
MANE Select: NM_152311
Type: single nucleotide variant
Location: chr10:127883833 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.68

Full CLRN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLRN3 p.Ala149Glu Uncertain significance ★ ⚠ same type
CLRN3 p.Ala149Ser Uncertain significance ★ ⚠ same type
CLRN3 p.Ala149Thr Uncertain significance ★ ⚠ same type
CLRN3 p.Ala149Val Uncertain significance ★ ⚠ same type
CLRN3 p.Arg208Trp Uncertain significance ★ ⚠ same type
CLRN3 p.Asn46His Uncertain significance ★ ⚠ same type
CLRN3 p.Gln207Arg Uncertain significance ★ ⚠ same type
CLRN3 p.Gln31Pro 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/clrn3-p-ser91leu (accessed [today's date]).

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