Is ARMC9 p.Pro520Ser (c.1558C>T) pathogenic?

ARMC9 p.Pro520Ser (c.1558C>T) is classified Uncertain significance in ARMC9 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-21). AlphaMissense: ambiguous (0.4329); Very rare (popmax 0.0011%, sas).

How common is ARMC9 p.Pro520Ser (c.1558C>T) in the general population?

ARMC9 p.Pro520Ser (c.1558C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ARMC9 p.Pro520Ser (c.1558C>T)?

AlphaMissense predicts ambiguous (score 0.4329) — an in-silico prediction, not a clinical call.

ARMC9 p.Pro520Ser

c.1558C>T · rs757757965 · VCV1490151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4329 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4329	ambiguous
REVEL	0.07	moderately benign-leaning
SaProt	LLR -9.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 165 kb · p 0.0061 · regional, not allelic
Overall
CADD	21.5	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 0.0011% South Asian · 1/91,068 alleles

Overall 0.000124% 2/1,613,986 alleles · very rare exomes 2/1,461,728 · genomes 0/152,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,068
European (non-Finnish)	8.48e-05%	1,179,934

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: ARMC9
Protein: p.Pro520Ser
Coding: c.1558C>T
MANE Select: NM_001352754
dbSNP: rs757757965
Type: single nucleotide variant
Location: chr2:231282065 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.71
Residue 520: a UniProt-annotated variant site (in jbts30; uncertain significance)

Full ARMC9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARMC9 p.Pro520= Benign/Likely benign ★★ same residue
ARMC9 p.Pro520Leu Pathogenic/Likely pathogenic ⚠ same residue
ARMC9 c.1773+1G>A Likely pathogenic ★★ same type
ARMC9 c.178-1G>A Likely pathogenic ★★ same type
ARMC9 c.178-2A>C Likely pathogenic ★★ same type
ARMC9 p.Arg299Ter Pathogenic/Likely pathogenic ★★ same type
ARMC9 p.Arg343Cys Pathogenic/Likely pathogenic ★★ same type
ARMC9 p.Arg87Ter 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/armc9-p-pro520ser (accessed [today's date]).

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