Is CLSPN p.Val61Phe (c.181G>T) pathogenic?

CLSPN p.Val61Phe (c.181G>T) is classified Uncertain significance in CLSPN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-27). AlphaMissense: likely benign (0.1074); Rare (popmax 0.109%, sas).

How common is CLSPN p.Val61Phe (c.181G>T) in the general population?

CLSPN p.Val61Phe (c.181G>T) is rare (popmax 0.109%, sas) (gnomAD).

What do computational predictors say about CLSPN p.Val61Phe (c.181G>T)?

AlphaMissense predicts likely benign (score 0.1074) — an in-silico prediction, not a clinical call.

CLSPN p.Val61Phe

c.181G>T · rs148367321 · VCV2382930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1074 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.109%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1074	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -6.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.87	GERP 0.07, phastCons 0.72
Regional constraint	o/e 0.92	unconstrained · MANE · 27 kb · p 0.005 · regional, not allelic
Overall
CADD	13.09	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 0.109% South Asian · 93/85,058 alleles

Filtering AF 0.0913% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0846%

Overall 0.0193% 307/1,590,078 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.109%	915
Remaining individualsnot grpmax-eligible	0.0293%	3,413
European (non-Finnish)	0.0164%	6,112
East Asian	0.00448%	22,323
Finnishnot grpmax-eligible	0.00157%	63,568
African / African-American	0.00136%	73,384

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: CLSPN
Protein: p.Val61Phe
Coding: c.181G>T
MANE Select: NM_022111
dbSNP: rs148367321
Type: single nucleotide variant
Location: chr1:35764667 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 51.32 · 5 PDB
Residue 61: the 'disordered' region

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

Similar variants

CLSPN p.Lys338= Benign ★★ same type
CLSPN p.Ala1222Asp Uncertain significance ★ ⚠ same type
CLSPN p.Ala126Val Uncertain significance ★ ⚠ same type
CLSPN p.Ala1295Val Uncertain significance ★ ⚠ same type
CLSPN p.Ala379Val Uncertain significance ★ ⚠ same type
CLSPN p.Ala450Thr Uncertain significance ★ ⚠ same type
CLSPN p.Ala543Pro Uncertain significance ★ ⚠ same type
CLSPN p.Ala578Thr 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/clspn-p-val61phe (accessed [today's date]).

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