Is CLSPN p.Ser954Phe (c.2861C>T) pathogenic?

CLSPN p.Ser954Phe (c.2861C>T) is classified Uncertain significance in CLSPN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.1179); Very rare (popmax 0.00528%, nfe).

How common is CLSPN p.Ser954Phe (c.2861C>T) in the general population?

CLSPN p.Ser954Phe (c.2861C>T) is very rare (popmax 0.00528%, nfe) (gnomAD).

What do computational predictors say about CLSPN p.Ser954Phe (c.2861C>T)?

AlphaMissense predicts likely benign (score 0.1179) — an in-silico prediction, not a clinical call.

CLSPN p.Ser954Phe

c.2861C>T · VCV4003842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1179 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00528%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1179	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -8.00	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 5.8	GERP 1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 27 kb · p 0.005 · regional, not allelic
Overall
CADD	22.5	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 0.00528% European (non-Finnish) · 62/1,174,210 alleles

Filtering AF 0.0042% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00411% 66/1,607,558 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00528%	18,939
African / African-American	0.00267%	37,396
Admixed American	0.00167%	59,984
Remaining individualsnot grpmax-eligible	0.00161%	62,272

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.Ser954Phe
Coding: c.2861C>T
MANE Select: NM_022111
Type: single nucleotide variant
Location: chr1:35745556 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 51.32 · 5 PDB
Residue 954: the 'disordered' region; a modified residue (phosphoserine)

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-ser954phe (accessed [today's date]).

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