Is ARMC8 p.Phe121Leu (c.363T>A) pathogenic?

ARMC8 p.Phe121Leu (c.363T>A) is classified Uncertain significance in ARMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: likely pathogenic (0.9207); Very rare (popmax 8.47e-05%, nfe).

How common is ARMC8 p.Phe121Leu (c.363T>A) in the general population?

ARMC8 p.Phe121Leu (c.363T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ARMC8 p.Phe121Leu (c.363T>A)?

AlphaMissense predicts likely pathogenic (score 0.9207) — an in-silico prediction, not a clinical call.

ARMC8 p.Phe121Leu

c.363T>A · rs745809184 · VCV2318430

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9207	likely pathogenic
REVEL	0.277	benign-leaning
SaProt	LLR -5.25	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 0.49	GERP 1.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 54 kb · p 0.012 · regional, not allelic
Overall
CADD	18.97	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 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,876 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: ARMC8
Protein: p.Phe121Leu
Coding: c.363T>A
MANE Select: NM_001363941
dbSNP: rs745809184
Type: single nucleotide variant
Location: chr3:138223661 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.16 · 1 PDB
Residue 121: an α-helix

Full ARMC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARMC8 p.Ala403Thr Uncertain significance ★ ⚠ same type
ARMC8 p.Ala469Thr Uncertain significance ★ ⚠ same type
ARMC8 p.Arg159Lys Uncertain significance ★ ⚠ same type
ARMC8 p.Arg161His Uncertain significance ★ ⚠ same type
ARMC8 p.Arg270Gln Uncertain significance ★ ⚠ same type
ARMC8 p.Arg270Trp Uncertain significance ★ ⚠ same type
ARMC8 p.Arg376Trp Uncertain significance ★ ⚠ same type
ARMC8 p.Arg542Cys Uncertain significance ★ ⚠ 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/armc8-p-phe121leu (accessed [today's date]).

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