Is HAP1 p.Leu408Phe (c.1224G>T) pathogenic?

HAP1 p.Leu408Phe (c.1224G>T) is classified Benign in HAP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-16). AlphaMissense: ambiguous (0.4723); Common (popmax 39.4%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with HAP1-related disorder.

What condition is associated with HAP1 p.Leu408Phe (c.1224G>T)?

HAP1 p.Leu408Phe (c.1224G>T) is associated with HAP1-related disorder (ClinVar).

What do computational predictors say about HAP1 p.Leu408Phe (c.1224G>T)?

AlphaMissense predicts ambiguous (score 0.4723) — an in-silico prediction, not a clinical call.

HAP1 p.Leu408Phe

Q: How common is HAP1 p.Leu408Phe (c.1224G>T) in the general population?

HAP1 p.Leu408Phe (c.1224G>T) is common (popmax 39.4%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1224G>T · rs35612698 · VCV3059732

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4723 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 39.4%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

HAP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4723	ambiguous
REVEL	0.198	benign-leaning
SaProt	LLR -10.06	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -2.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	21.8	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 39.4% European (non-Finnish) · 461,434/1,171,468 alleles

Filtering AF 39.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 39.3%

Overall 35.5% 569,155/1,603,770 alleles · common exomes 522,279/1,451,602 · genomes 46,876/152,168 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	52.3%	2
European (non-Finnish)grpmax	39.4%	3
Ashkenazi Jewishnot grpmax-eligible	35.4%	3
Middle Eastern	35.4%	3
Remaining individualsnot grpmax-eligible	34.1%	3
Finnishnot grpmax-eligible	28.5%	4
Admixed American	22.2%	4
South Asian	20.6%	5
African / African-American	20.2%	5
East Asian	18.5%	5

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: HAP1
Protein: p.Leu408Phe
Coding: c.1224G>T
MANE Select: NM_177977
dbSNP: rs35612698
Type: single nucleotide variant
Location: chr17:41727813 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 408: the hap1 n-terminal domain; a UniProt-annotated variant site (in)

Full HAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

HAP1-related disorder

Similar variants

HAP1 c.1201-4C>T Likely benign same condition
HAP1 c.1201-7C>T Likely benign same condition
HAP1 c.470-7C>G Likely benign same condition
HAP1 p.Ala21= Likely benign same condition
HAP1 p.Ala505Val Benign same condition
HAP1 p.Arg116Trp Likely benign same condition
HAP1 p.Asp339Asn Likely benign same condition
HAP1 p.Pro187His Likely benign 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/hap1-p-leu408phe (accessed [today's date]).

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