Is TRIP11 p.Arg423Ser (c.1267C>A) pathogenic?

TRIP11 p.Arg423Ser (c.1267C>A) is classified Uncertain significance in TRIP11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.1763); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with TRIP11 p.Arg423Ser (c.1267C>A)?

TRIP11 p.Arg423Ser (c.1267C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TRIP11 p.Arg423Ser (c.1267C>A) in the general population?

TRIP11 p.Arg423Ser (c.1267C>A) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about TRIP11 p.Arg423Ser (c.1267C>A)?

AlphaMissense predicts likely benign (score 0.1763) — an in-silico prediction, not a clinical call.

TRIP11 p.Arg423Ser

c.1267C>A · VCV4633622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1763 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1763	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -4.85	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 3.1	GERP 0.23, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 70 kb · p 0.00015 · regional, not allelic
Overall
CADD	13.6	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 0.00334% Admixed American · 2/59,958 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,613,540 alleles · very rare exomes 2/1,461,758 · genomes 1/151,782 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,979
African / African-American	0.00134%	74,756

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: TRIP11
Protein: p.Arg423Ser
Coding: c.1267C>A
MANE Select: NM_004239
Type: single nucleotide variant
Location: chr14:92011033 (GRCh38)
Gene constraint: LOEUF 0.731 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.78
Residue 423: a UniProt-annotated variant site (in odcd1; due to a nucleotide substitution that causes protein truncation or in-frame exon 4 skipping); a UniProt-annotated variant site (in acg1a and odcd1)

Full TRIP11 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

TRIP11 p.Arg423Cys Uncertain significance ★ ⚠ same residue
TRIP11 p.Arg423His Uncertain significance ★ ⚠ same residue
TRIP11 p.Ala1127Val Uncertain significance ★★ ⚠ same condition
TRIP11 p.Ala414Ser Uncertain significance ★★ ⚠ same condition
TRIP11 p.Ala459Thr Uncertain significance ★★ ⚠ same condition
TRIP11 p.Ala880Thr Uncertain significance ★★ ⚠ same condition
TRIP11 p.Arg1576Cys Uncertain significance ★★ ⚠ same condition
TRIP11 p.Arg1926Cys 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/trip11-p-arg423ser (accessed [today's date]).

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