Is CTSK p.Ser271Asn (c.812G>A) pathogenic?

CTSK p.Ser271Asn (c.812G>A) is classified Uncertain significance in CTSK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-04-11). AlphaMissense: likely benign (0.1244); Ultra-rare (popmax 0.033%, mid); Associated with pycnodysostosis.

What condition is associated with CTSK p.Ser271Asn (c.812G>A)?

CTSK p.Ser271Asn (c.812G>A) is associated with pycnodysostosis (ClinVar).

How common is CTSK p.Ser271Asn (c.812G>A) in the general population?

CTSK p.Ser271Asn (c.812G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Pycnodysostosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTSK p.Ser271Asn (c.812G>A)?

AlphaMissense predicts likely benign (score 0.1244) — an in-silico prediction, not a clinical call.

CTSK p.Ser271Asn

c.812G>A · rs183135762 · VCV292581

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1244 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pycnodysostosis

Computational evidence

Protein change
AlphaMissense	0.1244	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 2.7	GERP 2, phastCons 0.027
Regional constraint	o/e 0.73	unconstrained · MANE · 10 kb · p 6.6e-08 · regional, not allelic
Overall
CADD	18.97	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.0164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0156%

Overall 0.015% 242/1,613,054 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
European (non-Finnish)	0.0184%	5,433
Remaining individualsnot grpmax-eligible	0.016%	6,248
Admixed American	0.0117%	8,573
South Asian	0.00439%	22,763
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Finnishnot grpmax-eligible	0.00156%	64,016

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: CTSK
Protein: p.Ser271Asn
Coding: c.812G>A
MANE Select: NM_000396
dbSNP: rs183135762
Type: single nucleotide variant
Location: chr1:150799246 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.89 · 70 PDB
Residue 271: a disulfide bond

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

Disease context

pycnodysostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pycnodysostosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CTSK p.Ser271= Likely benign ★ same residue
CTSK c.121-1G>A Pathogenic/Likely pathogenic ★★ same condition
CTSK c.121-2A>G Pathogenic/Likely pathogenic ★★ same condition
CTSK c.244-29A>G Pathogenic/Likely pathogenic ★★ same condition
CTSK c.400-1G>C Likely pathogenic ★★ same condition
CTSK c.784+1G>A Likely pathogenic ★★ same condition
CTSK p.Ala277Val Pathogenic ★★ same condition
CTSK p.Arg122Ter Pathogenic/Likely pathogenic ★★ same condition

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/ctsk-p-ser271asn (accessed [today's date]).

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