Is CLRN1 p.Pro127Thr (c.379C>A) pathogenic?

CLRN1 p.Pro127Thr (c.379C>A) is classified Uncertain significance in CLRN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-27). AlphaMissense: likely benign (0.3308); Very rare (popmax 0.00161%, nfe).

How common is CLRN1 p.Pro127Thr (c.379C>A) in the general population?

CLRN1 p.Pro127Thr (c.379C>A) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about CLRN1 p.Pro127Thr (c.379C>A)?

AlphaMissense predicts likely benign (score 0.3308) — an in-silico prediction, not a clinical call.

CLRN1 p.Pro127Thr

c.379C>A · rs766352408 · VCV2157669

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3308 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3308	likely benign
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -6.83	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 45 kb · p 0.044 · regional, not allelic
Overall
CADD	26.1	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 0.00161% European (non-Finnish) · 19/1,179,958 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,613,918 alleles · very rare

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: CLRN1
Protein: p.Pro127Thr
Coding: c.379C>A
MANE Select: NM_174878
dbSNP: rs766352408
Type: single nucleotide variant
Location: chr3:150941636 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.74

Full CLRN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLRN1 p.Pro127Arg Uncertain significance ★★ ⚠ same residue
CLRN1 c.253+1G>A Likely pathogenic ★★ same type
CLRN1 c.253+6T>C Pathogenic/Likely pathogenic ★★ same type
CLRN1 c.254-2A>G Pathogenic/Likely pathogenic ★★ same type
CLRN1 c.254-649T>G Pathogenic/Likely pathogenic ★★ same type
CLRN1 c.433+1G>A Pathogenic/Likely pathogenic ★★ same type
CLRN1 c.433+1G>T Likely pathogenic ★★ same type
CLRN1 p.Ala123Asp Pathogenic/Likely pathogenic ★★ 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/clrn1-p-pro127thr (accessed [today's date]).

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