Is CHCHD4 p.Phe68Leu (c.204T>G) pathogenic?

CHCHD4 p.Phe68Leu (c.204T>G) is classified Uncertain significance in CHCHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1.

How common is CHCHD4 p.Phe68Leu (c.204T>G) in the general population?

CHCHD4 p.Phe68Leu (c.204T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHCHD4 p.Phe68Leu (c.204T>G)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

CHCHD4 p.Phe68Leu

c.204T>G · VCV4227691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 1% in CHCHD4
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -13.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.34	acceptor loss, 30 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 4.2	GERP -1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 12 kb · p 0.015 · regional, not allelic
Overall
CADD	23.6	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: CHCHD4
Protein: p.Phe68Leu
Coding: c.204T>G
MANE Select: NM_001098502
Type: single nucleotide variant
Location: chr3:14113112 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 75.55 · 4 PDB
Residue 68: the chch domain; an α-helix; a disulfide bond

Full CHCHD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHCHD4 c.122-7G>A Benign ★★ same type
TMEM43 c.-414C>T Benign ★★ same type
CHCHD4 c.22+2688C>T Uncertain significance ★ same type
CHCHD4 c.22+2693T>C Uncertain significance ★ same type
CHCHD4 c.22+2729G>A Uncertain significance ★ same type
CHCHD4 p.Ala121Pro Uncertain significance ★ ⚠ same type
CHCHD4 p.Arg116Gly Uncertain significance ★ ⚠ same type
CHCHD4 p.Arg92Gln 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/chchd4-p-phe68leu (accessed [today's date]).

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