Is ARMC5 p.Phe439Leu (c.1317T>A) pathogenic?

ARMC5 p.Phe439Leu (c.1317T>A) is classified Uncertain significance in ARMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). AlphaMissense: likely pathogenic (0.9484); Very rare (popmax 0.0017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ARMC5 p.Phe439Leu (c.1317T>A)?

ARMC5 p.Phe439Leu (c.1317T>A) is associated with Inborn genetic diseases (ClinVar).

How common is ARMC5 p.Phe439Leu (c.1317T>A) in the general population?

ARMC5 p.Phe439Leu (c.1317T>A) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about ARMC5 p.Phe439Leu (c.1317T>A)?

AlphaMissense predicts likely pathogenic (score 0.9484) — an in-silico prediction, not a clinical call.

ARMC5 p.Phe439Leu

c.1317T>A · VCV3315635

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9484	likely pathogenic · top 8% in ARMC5
REVEL	0.17	moderately benign-leaning
SaProt	LLR -4.62	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.041	GERP -2.1, phastCons 0.91
Regional constraint	o/e 0.80	unconstrained · MANE · 4,961 bp · p 1.6e-10 · regional, not allelic
Overall
CADD	19.67	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 0.0017% European (non-Finnish) · 20/1,179,772 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00124% 20/1,613,332 alleles · very rare

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.Phe439Leu
Coding: c.1317T>A
MANE Select: NM_001105247
Type: single nucleotide variant
Location: chr16:31462864 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 439: the 'disordered' region; a UniProt-annotated variant site (in aimah2; uncertain significance); a UniProt-annotated variant site (in aimah2)

Full ARMC5 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

Similar variants

ARMC5 p.Phe439= Benign ★ same residue
ARMC5 p.Ala55Val Uncertain significance ★★ ⚠ same condition
ARMC5 p.Arg611Leu Uncertain significance ★★ ⚠ same condition
ARMC5 p.Ser266Thr Uncertain significance ★★ ⚠ same condition
ARMC5 p.Trp801Cys Uncertain significance ★★ ⚠ same condition
ARMC5 p.Ala100Thr Uncertain significance ★ ⚠ same condition
ARMC5 p.Ala206Ser Uncertain significance ★ ⚠ same condition
ARMC5 p.Ala22Val 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/armc5-p-phe439leu (accessed [today's date]).

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