Is PEX1 p.Arg577Cys (c.1729C>T) pathogenic?

PEX1 p.Arg577Cys (c.1729C>T) is classified Uncertain significance in PEX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-14). AlphaMissense: likely benign (0.1458); Very rare (popmax 0.0022%, sas).

How common is PEX1 p.Arg577Cys (c.1729C>T) in the general population?

PEX1 p.Arg577Cys (c.1729C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about PEX1 p.Arg577Cys (c.1729C>T)?

AlphaMissense predicts likely benign (score 0.1458) — an in-silico prediction, not a clinical call.

PEX1 p.Arg577Cys

c.1729C>T · VCV4896712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1458 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1458	likely benign
REVEL	0.611	indeterminate
SaProt	LLR -4.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP 4.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	25.8	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 0.0022% South Asian · 2/91,062 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000806% 13/1,613,762 alleles · very rare exomes 13/1,461,548 · genomes 0/152,214 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,531
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000848%	117,973

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: PEX1
Protein: p.Arg577Cys
Coding: c.1729C>T
MANE Select: NM_000466
Type: single nucleotide variant
Location: chr7:92507068 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.19

Full PEX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PEX1 p.Arg577His Uncertain significance ★ ⚠ same residue
PEX1 p.Arg577Ser Uncertain significance ★ same residue
PEX1 p.Arg577= Likely benign ★ same residue
PEX1 p.Arg577fs Likely pathogenic ★ same residue
PEX1 c.1239+1G>T Pathogenic ★★ same type
PEX1 c.130-1G>T Pathogenic/Likely pathogenic ★★ same type
PEX1 c.130-2A>G Pathogenic/Likely pathogenic ★★ same type
PEX1 c.130-2A>T Pathogenic/Likely pathogenic ★★ 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/pex1-p-arg577cys (accessed [today's date]).

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