Is ARMC8 p.Pro249Ser (c.745C>T) pathogenic?

ARMC8 p.Pro249Ser (c.745C>T) is classified Uncertain significance in ARMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-01). AlphaMissense: ambiguous (0.3926); Very rare (popmax 0.00381%, nfe).

How common is ARMC8 p.Pro249Ser (c.745C>T) in the general population?

ARMC8 p.Pro249Ser (c.745C>T) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about ARMC8 p.Pro249Ser (c.745C>T)?

AlphaMissense predicts ambiguous (score 0.3926) — an in-silico prediction, not a clinical call.

ARMC8 p.Pro249Ser

c.745C>T · VCV3431075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3926	ambiguous
REVEL	0.212	benign-leaning
SaProt	LLR -7.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 54 kb · p 0.012 · regional, not allelic
Overall
CADD	24.5	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 0.00381% European (non-Finnish) · 45/1,179,916 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00285% 46/1,613,292 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,220
African / African-American	0.00134%	74,888

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.Pro249Ser
Coding: c.745C>T
MANE Select: NM_001363941
Type: single nucleotide variant
Location: chr3:138237541 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.16 · 1 PDB

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-pro249ser (accessed [today's date]).

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