Is RNF125 p.Ser59Phe (c.176C>T) pathogenic?

RNF125 p.Ser59Phe (c.176C>T) is classified Likely benign in RNF125 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-15). AlphaMissense: likely benign (0.3028); Ultra-rare (popmax 0.0539%, sas); Associated with Inborn genetic diseases.

What condition is associated with RNF125 p.Ser59Phe (c.176C>T)?

RNF125 p.Ser59Phe (c.176C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RNF125 p.Ser59Phe (c.176C>T) in the general population?

RNF125 p.Ser59Phe (c.176C>T) is ultra-rare (popmax 0.0539%, sas) (gnomAD).

What do computational predictors say about RNF125 p.Ser59Phe (c.176C>T)?

AlphaMissense predicts likely benign (score 0.3028) — an in-silico prediction, not a clinical call.

RNF125 p.Ser59Phe

c.176C>T · rs757825021 · VCV2226586

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0539%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3028	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -5.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 50 kb · p 0.09 · regional, not allelic
Overall
CADD	27.4	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 0.0539% South Asian · 48/89,044 alleles

Filtering AF 0.0417% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0374%

Overall 0.00306% 49/1,602,484 alleles · ultra-rare exomes 47/1,450,448 · genomes 2/152,036 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0539%	1,855
Remaining individualsnot grpmax-eligible	0.00161%	62,024

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: RNF125
Protein: p.Ser59Phe
Coding: c.176C>T
MANE Select: NM_017831
dbSNP: rs757825021
Type: single nucleotide variant
Location: chr18:32037127 (GRCh38)
Gene constraint: LOEUF 1.071 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 3 PDB
Residue 59: an α-helix

Full RNF125 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RNF125 p.Ser59Pro Uncertain significance ★★ ⚠ same residue
RNF125 p.Arg220Gln Uncertain significance ★★ ⚠ same condition
RNF125 p.Ile123Thr Uncertain significance ★★ ⚠ same condition
RNF125 p.Pro128Thr Uncertain significance ★★ ⚠ same condition
RNF125 p.Asn67Ile Uncertain significance ★ ⚠ same condition
RNF125 p.Asp178Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
RNF125 p.Cys173Tyr Uncertain significance ★ ⚠ same condition
RNF125 p.Gln130Arg Uncertain significance ★ ⚠ same condition

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/rnf125-p-ser59phe (accessed [today's date]).

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