Is ARMC5 p.Pro559Leu (c.1676C>T) pathogenic?

ARMC5 p.Pro559Leu (c.1676C>T) is classified Likely benign in ARMC5 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1342); Rare (popmax 0.187%, nfe).

How common is ARMC5 p.Pro559Leu (c.1676C>T) in the general population?

ARMC5 p.Pro559Leu (c.1676C>T) is rare (popmax 0.187%, nfe) (gnomAD).

What do computational predictors say about ARMC5 p.Pro559Leu (c.1676C>T)?

AlphaMissense predicts likely benign (score 0.1342) — an in-silico prediction, not a clinical call.

ARMC5 p.Pro559Leu

c.1676C>T · rs200115942 · VCV782788

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1342 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.187%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1342	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -8.79	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 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,961 bp · p 1.6e-10 · regional, not allelic
Overall
CADD	21.9	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 0.187% European (non-Finnish) · 2,202/1,179,076 alleles

Filtering AF 0.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.15% 2,393/1,598,602 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.32%	76
European (non-Finnish)grpmax	0.187%	535
Remaining individualsnot grpmax-eligible	0.0979%	1,022
Finnishnot grpmax-eligible	0.0859%	1,163
Admixed American	0.0634%	1,577
African / African-American	0.036%	2,778
East Asian	0.0156%	6,403
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,839

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ARMC5
Protein: p.Pro559Leu
Coding: c.1676C>T
MANE Select: NM_001105247
dbSNP: rs200115942
Type: single nucleotide variant
Location: chr16:31464699 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 559: a UniProt-annotated variant site (in aimah2; uncertain significance); a UniProt-annotated variant site (in aimah2); a UniProt-annotated variant site (found in patients with myelomeningocele; decreased association with polr2a component of rna polymerase ii)

Full ARMC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARMC5 p.Arg173Ter Pathogenic ★★ same type
ARMC5 p.Ala55Val Uncertain significance ★★ ⚠ same type
ARMC5 p.Arg611Leu Uncertain significance ★★ ⚠ same type
ARMC5 p.Arg690Gln Uncertain significance ★★ ⚠ same type
ARMC5 p.Pro606Leu Uncertain significance ★★ ⚠ same type
ARMC5 p.Ser266Thr Uncertain significance ★★ ⚠ same type
ARMC5 p.Trp801Cys Uncertain significance ★★ ⚠ same type
ARMC5 p.Ala110Thr Benign/Likely benign ★★ 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/armc5-p-pro559leu (accessed [today's date]).

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