Is FECH p.Lys379Arg (c.1136A>G) pathogenic?

FECH p.Lys379Arg (c.1136A>G) is classified Uncertain significance in FECH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-27). AlphaMissense: likely benign (0.0768); Absent from gnomAD v4.1.

How common is FECH p.Lys379Arg (c.1136A>G) in the general population?

FECH p.Lys379Arg (c.1136A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FECH p.Lys379Arg (c.1136A>G)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

FECH p.Lys379Arg

c.1136A>G · rs2511512445 · VCV2763632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.93	donor loss · deltas
Pangolin	Δ0.80	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	23.3	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: FECH
Protein: p.Lys379Arg
Coding: c.1136A>G
MANE Select: NM_000140
dbSNP: rs2511512445
Type: single nucleotide variant
Location: chr18:57551316 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB
Residue 379: a UniProt-annotated variant site (in epp1; enzyme retains 37% of activity); an α-helix

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

Similar variants

FECH p.Lys379fs Pathogenic/Likely pathogenic ★★ same residue
FECH c.1137+3A>G Pathogenic/Likely pathogenic ★★ same type
FECH c.314+2T>G Pathogenic/Likely pathogenic ★★ same type
FECH c.463+1G>C Pathogenic ★★ same type
FECH c.598+1G>T Pathogenic ★★ same type
FECH c.599-2A>G Pathogenic ★★ same type
FECH c.913-2A>G Likely pathogenic ★★ same type
FECH p.Arg115Ter 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/fech-p-lys379arg (accessed [today's date]).

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