Is CHAF1A p.Pro586Arg (c.1757C>G) pathogenic?

CHAF1A p.Pro586Arg (c.1757C>G) is classified Uncertain significance in CHAF1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.9181); Absent from gnomAD v4.1.

How common is CHAF1A p.Pro586Arg (c.1757C>G) in the general population?

CHAF1A p.Pro586Arg (c.1757C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHAF1A p.Pro586Arg (c.1757C>G)?

AlphaMissense predicts likely pathogenic (score 0.9181) — an in-silico prediction, not a clinical call.

CHAF1A p.Pro586Arg

c.1757C>G · VCV4278728

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9181 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9181	likely pathogenic · top 8% in CHAF1A
REVEL	0.641	indeterminate
SaProt	LLR -12.63	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,368 bp · p 0.16 · regional, not allelic
Overall
CADD	24.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHAF1A
Protein: p.Pro586Arg
Coding: c.1757C>G
MANE Select: NM_005483
Type: single nucleotide variant
Location: chr19:4429590 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.06 · 11 PDB

Full CHAF1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

UBXN6 p.Arg313Leu Uncertain significance ★★ ⚠ same type
CHAF1A p.Ala70= Benign ★★ same type
CHAF1A p.Trp668Ter Pathogenic ★ same type
CHAF1A p.Ala140Gly Uncertain significance ★ ⚠ same type
CHAF1A p.Ala16Pro Uncertain significance ★ ⚠ same type
CHAF1A p.Ala193Ser Uncertain significance ★ ⚠ same type
CHAF1A p.Ala193Thr Uncertain significance ★ ⚠ same type
CHAF1A p.Ala247Pro 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/chaf1a-p-pro586arg (accessed [today's date]).

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