Is ARMC5 p.Leu778Pro (c.2333T>C) pathogenic?

ARMC5 p.Leu778Pro (c.2333T>C) is classified Uncertain significance in ARMC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-14). AlphaMissense: likely pathogenic (0.9682); Very rare (popmax 8.48e-05%, nfe).

How common is ARMC5 p.Leu778Pro (c.2333T>C) in the general population?

ARMC5 p.Leu778Pro (c.2333T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ARMC5 p.Leu778Pro (c.2333T>C)?

AlphaMissense predicts likely pathogenic (score 0.9682) — an in-silico prediction, not a clinical call.

ARMC5 p.Leu778Pro

c.2333T>C · VCV3343087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9682	likely pathogenic · top 5% in ARMC5
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -14.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	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	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,846 alleles

Overall 6.85e-05% 1/1,459,924 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.Leu778Pro
Coding: c.2333T>C
MANE Select: NM_001105247
Type: single nucleotide variant
Location: chr16:31466414 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 778: a UniProt-annotated variant site (in aimah2; uncertain significance); a UniProt-annotated variant site (in aimah2); the btb domain

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-leu778pro (accessed [today's date]).

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