Is CLRN3 p.Ala149Val (c.446C>T) pathogenic?

CLRN3 p.Ala149Val (c.446C>T) is classified Uncertain significance in CLRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: likely benign (0.0803); Ultra-rare (popmax 0.0296%, sas).

How common is CLRN3 p.Ala149Val (c.446C>T) in the general population?

CLRN3 p.Ala149Val (c.446C>T) is ultra-rare (popmax 0.0296%, sas) (gnomAD).

What do computational predictors say about CLRN3 p.Ala149Val (c.446C>T)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

CLRN3 p.Ala149Val

c.446C>T · VCV3834137

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0296%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.214	benign-leaning
SaProt	LLR -4.62	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 -0.2	GERP -2.7
Regional constraint	o/e 1.08	unconstrained · MANE · 15 kb · p 0.19 · regional, not allelic
Overall
CADD	0.696	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 0.0296% South Asian · 27/91,090 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00527% 85/1,614,044 alleles · ultra-rare exomes 82/1,461,872 · genomes 3/152,172 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0296%	3,374
East Asian	0.00668%	14,965
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00424%	23,601
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed American	0.00167%	59,994

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.Ala149Val
Coding: c.446C>T
MANE Select: NM_152311
Type: single nucleotide variant
Location: chr10:127878384 (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 residue
CLRN3 p.Ala149Ser Uncertain significance ★ ⚠ same residue
CLRN3 p.Ala149Thr Uncertain significance ★ ⚠ same residue
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
CLRN3 p.Glu158Lys 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-ala149val (accessed [today's date]).

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