Is ARMS2 p.Phe80Leu (c.240C>A) pathogenic?

ARMS2 p.Phe80Leu (c.240C>A) is classified Uncertain significance in ARMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.7817); Very rare (popmax 0.000254%, nfe).

How common is ARMS2 p.Phe80Leu (c.240C>A) in the general population?

ARMS2 p.Phe80Leu (c.240C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ARMS2 p.Phe80Leu (c.240C>A)?

AlphaMissense predicts likely pathogenic (score 0.7817) — an in-silico prediction, not a clinical call.

ARMS2 p.Phe80Leu

c.240C>A · VCV4147597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7817	likely pathogenic · top 1% in ARMS2
REVEL	0.032	moderately benign-leaning
SaProt	LLR -5.05	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 -0.23	GERP -0.15
Regional constraint	o/e 0.78	unconstrained · MANE · 2,202 bp · p 0.011 · regional, not allelic
Overall
CADD	0.471	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 0.000254% European (non-Finnish) · 3/1,179,704 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,424 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: ARMS2
Protein: p.Phe80Leu
Coding: c.240C>A
MANE Select: NM_001099667
Type: single nucleotide variant
Location: chr10:122454967 (GRCh38)
Gene constraint: LOEUF 1.815 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 58.14

Full ARMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARMS2 c.298-13A>G Benign/Likely benign ★★ same type
ARMS2 c.298-13A>T Benign/Likely benign ★★ same type
ARMS2 c.*107T>G Likely benign ★★ same type
ARMS2 c.*373T>G Benign/Likely benign ★★ same type
ARMS2 c.*45T>G Likely benign ★★ same type
ARMS2 p.Ala69Ser Benign ★★ same type
ARMS2 p.Arg38Ter Benign ★★ same type
ARMS2 c.*251T>C 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/arms2-p-phe80leu (accessed [today's date]).

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