Is ARCN1 p.Pro216Ser (c.646C>T) pathogenic?

ARCN1 p.Pro216Ser (c.646C>T) is classified Conflicting classifications of pathogenicity in ARCN1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-03-16). AlphaMissense: likely benign (0.064); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ARCN1 p.Pro216Ser (c.646C>T)?

ARCN1 p.Pro216Ser (c.646C>T) is associated with Inborn genetic diseases, short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (ClinVar).

How common is ARCN1 p.Pro216Ser (c.646C>T) in the general population?

ARCN1 p.Pro216Ser (c.646C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARCN1 p.Pro216Ser (c.646C>T)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

ARCN1 p.Pro216Ser

c.646C>T · rs2497685662 · VCV2556581

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -7.95	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 4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 17 kb · p 0.00011 · regional, not allelic
Overall
CADD	21.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ARCN1
Protein: p.Pro216Ser
Coding: c.646C>T
MANE Select: NM_001655
dbSNP: rs2497685662
Type: single nucleotide variant
Location: chr11:118584007 (GRCh38)
Gene constraint: LOEUF 0.145 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.25

Full ARCN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay

Similar variants

ARCN1 c.654-15A>G Pathogenic/Likely pathogenic ★★ same condition
ARCN1 p.Arg170Ter Pathogenic ★★ same condition
ARCN1 p.Arg312Ter Pathogenic ★★ same condition
ARCN1 p.Arg161His Uncertain significance ★★ ⚠ same condition
ARCN1 p.Arg314His Uncertain significance ★★ ⚠ same condition
ARCN1 p.Asn348His Uncertain significance ★★ ⚠ same condition
ARCN1 p.Asp400Glu Uncertain significance ★★ ⚠ same condition
ARCN1 p.Asp426Asn Uncertain significance ★★ ⚠ 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/arcn1-p-pro216ser (accessed [today's date]).

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