Is FAH p.Pro414Arg (c.1241C>G) pathogenic?

FAH p.Pro414Arg (c.1241C>G) is classified Uncertain significance in FAH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely benign (0.2076); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with FAH p.Pro414Arg (c.1241C>G)?

FAH p.Pro414Arg (c.1241C>G) is associated with Inborn genetic diseases (ClinVar).

How common is FAH p.Pro414Arg (c.1241C>G) in the general population?

FAH p.Pro414Arg (c.1241C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about FAH p.Pro414Arg (c.1241C>G)?

AlphaMissense predicts likely benign (score 0.2076) — an in-silico prediction, not a clinical call.

FAH p.Pro414Arg

c.1241C>G · VCV4619075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2076	likely benign
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -13.39	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.029 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,874 alleles

Overall 0.000124% 2/1,614,010 alleles · very rare exomes 1/1,461,660 · genomes 1/152,350 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,874
European (non-Finnish)	8.48e-05%	1,179,842

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: FAH
Protein: p.Pro414Arg
Coding: c.1241C>G
MANE Select: NM_000137
Type: single nucleotide variant
Location: chr15:80186190 (GRCh38)
Gene constraint: LOEUF 1.067 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 98.06 · 8 PDB

Full FAH 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

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FAH c.82-3T>C Uncertain significance ★★ same condition
FAH p.Arg131Gln Uncertain significance ★★ ⚠ same condition
FAH p.Arg162His Uncertain significance ★★ ⚠ same condition
FAH p.Arg341Gln Uncertain significance ★★ ⚠ same condition
FAH p.Arg97Ser Uncertain significance ★★ ⚠ same condition
FAH p.Asn136Ser Uncertain significance ★★ ⚠ same condition
FAH p.Asn146Ser 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/fah-p-pro414arg (accessed [today's date]).

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