Is ARMC2 p.Pro99Leu (c.296C>T) pathogenic?

ARMC2 p.Pro99Leu (c.296C>T) is classified Uncertain significance in ARMC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.1757); Ultra-rare (popmax 0.0188%, sas).

How common is ARMC2 p.Pro99Leu (c.296C>T) in the general population?

ARMC2 p.Pro99Leu (c.296C>T) is ultra-rare (popmax 0.0188%, sas) (gnomAD).

What do computational predictors say about ARMC2 p.Pro99Leu (c.296C>T)?

AlphaMissense predicts likely benign (score 0.1757) — an in-silico prediction, not a clinical call.

ARMC2 p.Pro99Leu

c.296C>T · VCV4643038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1757 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1757	likely benign
REVEL	0.487	indeterminate
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 119 kb · p 0.00055 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0188% South Asian · 17/90,378 alleles

Filtering AF 0.0119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00983%

Overall 0.00178% 26/1,456,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0188%	5,316
African / African-American	0.00268%	37,305
Admixed American	0.00171%	58,396
Remaining individualsnot grpmax-eligible	0.00161%	62,212
European (non-Finnish)	0.000424%	235,704

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: ARMC2
Protein: p.Pro99Leu
Coding: c.296C>T
MANE Select: NM_032131
Type: single nucleotide variant
Location: chr6:108868828 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.57
Residue 99: the 'disordered' region

Full ARMC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARMC2 p.Pro99= Benign same residue
ARMC2 c.2153-1G>C Likely pathogenic ★ same type
ARMC2 p.Asn743Asp Likely pathogenic ★ same type
ARMC2 p.Ala123Val Uncertain significance ★ ⚠ same type
ARMC2 p.Ala143Thr Uncertain significance ★ ⚠ same type
ARMC2 p.Ala231Thr Uncertain significance ★ ⚠ same type
ARMC2 p.Ala260Pro Uncertain significance ★ ⚠ same type
ARMC2 p.Ala292Asp 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/armc2-p-pro99leu (accessed [today's date]).

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