Is KHDC3L p.Arg135Pro (c.404G>C) pathogenic?

KHDC3L p.Arg135Pro (c.404G>C) is classified Uncertain significance in KHDC3L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-26). AlphaMissense: likely benign (0.1485); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with KHDC3L p.Arg135Pro (c.404G>C)?

KHDC3L p.Arg135Pro (c.404G>C) is associated with Inborn genetic diseases (ClinVar).

How common is KHDC3L p.Arg135Pro (c.404G>C) in the general population?

KHDC3L p.Arg135Pro (c.404G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KHDC3L p.Arg135Pro (c.404G>C)?

AlphaMissense predicts likely benign (score 0.1485) — an in-silico prediction, not a clinical call.

KHDC3L p.Arg135Pro

c.404G>C · VCV3533285

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1485 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1485	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -9.90	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 -1.9	GERP -1.9
Regional constraint	o/e 1.01	unconstrained · MANE · 1,127 bp · p 0.88 · regional, not allelic
Overall
CADD	0.94	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

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: KHDC3L
Protein: p.Arg135Pro
Coding: c.404G>C
MANE Select: NM_001017361
Type: single nucleotide variant
Location: chr6:73363610 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI 0.12 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.69
Residue 135: the 'disordered' region

Full KHDC3L 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

KHDC3L p.Arg135Trp Uncertain significance ★ ⚠ same residue
KHDC3L p.Ala185Asp Uncertain significance ★ ⚠ same condition
KHDC3L p.Arg205Gln Uncertain significance ★ ⚠ same condition
KHDC3L p.Arg211Gln Uncertain significance ★ ⚠ same condition
KHDC3L p.Arg211Trp Uncertain significance ★ ⚠ same condition
KHDC3L p.Arg46Cys Uncertain significance ★ ⚠ same condition
KHDC3L p.Arg46Leu Uncertain significance ★ ⚠ same condition
KHDC3L p.Arg92Ser 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/khdc3l-p-arg135pro (accessed [today's date]).

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