Is FA2H p.Arg41Leu (c.122G>T) pathogenic?

FA2H p.Arg41Leu (c.122G>T) is classified Uncertain significance in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.1486); Very rare (popmax 0.00205%, amr); Associated with Inborn genetic diseases.

What condition is associated with FA2H p.Arg41Leu (c.122G>T)?

FA2H p.Arg41Leu (c.122G>T) is associated with Inborn genetic diseases (ClinVar).

How common is FA2H p.Arg41Leu (c.122G>T) in the general population?

FA2H p.Arg41Leu (c.122G>T) is very rare (popmax 0.00205%, amr) (gnomAD).

What do computational predictors say about FA2H p.Arg41Leu (c.122G>T)?

AlphaMissense predicts likely benign (score 0.1486) — an in-silico prediction, not a clinical call.

FA2H p.Arg41Leu

c.122G>T · VCV4619071

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00205%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1486	likely benign
REVEL	0.595	indeterminate
SaProt	LLR -4.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -0.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	26.4	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 0.00205% Admixed American · 1/48,818 alleles

Overall 0.000198% 3/1,513,174 alleles · very rare exomes 2/1,361,110 · genomes 1/152,064 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00205%	48,818
African / African-American	0.00143%	70,124
South Asian	0.00124%	80,968

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: FA2H
Protein: p.Arg41Leu
Coding: c.122G>T
MANE Select: NM_024306
Type: single nucleotide variant
Location: chr16:74774634 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 41: the cytochrome b5 heme-binding domain

Full FA2H 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

FA2H p.Arg189Ter Pathogenic ★★ same condition
FA2H c.363+5C>A Uncertain significance ★★ same condition
FA2H p.Arg151Gly Uncertain significance ★★ ⚠ same condition
FA2H p.Arg28Cys Uncertain significance ★★ ⚠ same condition
FA2H p.Gln289His Uncertain significance ★★ ⚠ same condition
FA2H p.Gln344Glu Uncertain significance ★★ ⚠ same condition
FA2H p.Gln344His Uncertain significance ★★ ⚠ same condition
FA2H p.Gly23Arg 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/fa2h-p-arg41leu (accessed [today's date]).

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