Is FECH p.His247Asp (c.739C>G) pathogenic?

FECH p.His247Asp (c.739C>G) is classified Uncertain significance in FECH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.1295); Ultra-rare (popmax 0.0109%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FECH p.His247Asp (c.739C>G)?

FECH p.His247Asp (c.739C>G) is associated with Inborn genetic diseases (ClinVar).

How common is FECH p.His247Asp (c.739C>G) in the general population?

FECH p.His247Asp (c.739C>G) is ultra-rare (popmax 0.0109%, nfe) (gnomAD).

What do computational predictors say about FECH p.His247Asp (c.739C>G)?

AlphaMissense predicts likely benign (score 0.1295) — an in-silico prediction, not a clinical call.

FECH p.His247Asp

c.739C>G · VCV4256713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1295 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1295	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -9.48	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 2.9	GERP -0.32, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 36 kb · p 2e-05 · regional, not allelic
Overall
CADD	20.1	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 0.0109% European (non-Finnish) · 129/1,179,642 alleles

Filtering AF 0.00936% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0088%

Overall 0.00812% 131/1,613,488 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0109%	9,145
Remaining individualsnot grpmax-eligible	0.0032%	31,235

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: FECH
Protein: p.His247Asp
Coding: c.739C>G
MANE Select: NM_000140
Type: single nucleotide variant
Location: chr18:57559210 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.37 · 25 PDB

Full FECH 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

FECH p.Leu4Phe Uncertain significance ★★ ⚠ same condition
FECH p.Lys320Arg Uncertain significance ★★ ⚠ same condition
FECH p.Met267Thr Uncertain significance ★★ ⚠ same condition
FECH p.Ser197Thr Uncertain significance ★★ ⚠ same condition
FECH p.Ser268Phe Uncertain significance ★★ ⚠ same condition
FECH p.Val166Ile Uncertain significance ★★ ⚠ same condition
FECH p.Asn105= Likely benign ★★ same condition
FECH p.Ala10Thr 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/fech-p-his247asp (accessed [today's date]).

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