Is HAP1 p.Pro37Leu (c.110C>T) pathogenic?

HAP1 p.Pro37Leu (c.110C>T) is classified Uncertain significance in HAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely benign (0.1332); Very rare (popmax 0.0011%, sas).

How common is HAP1 p.Pro37Leu (c.110C>T) in the general population?

HAP1 p.Pro37Leu (c.110C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about HAP1 p.Pro37Leu (c.110C>T)?

AlphaMissense predicts likely benign (score 0.1332) — an in-silico prediction, not a clinical call.

HAP1 p.Pro37Leu

c.110C>T · rs782246902 · VCV2620926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1332 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1332	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -7.54	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 2.5	GERP 0.35, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	16.76	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 0.0011% South Asian · 1/90,920 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,611,548 alleles · very rare exomes 8/1,459,340 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,920
European (non-Finnish)	0.000678%	147,457

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.Pro37Leu
Coding: c.110C>T
MANE Select: NM_177977
dbSNP: rs782246902
Type: single nucleotide variant
Location: chr17:41734525 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 37: the 'disordered' region

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

Similar variants

HAP1 p.Pro37Ser Uncertain significance ★ ⚠ same residue
HAP1 p.Arg106Pro Uncertain significance ★★ ⚠ same type
HAP1 p.Cys25Tyr Benign ★★ same type
HAP1 p.Gly604Arg Benign ★★ same type
HAP1 p.Ile496Val Benign ★★ same type
HAP1 p.Leu348= Benign ★★ same type
HAP1 p.Ser616Ter Benign ★★ same type
HAP1 p.Thr441Met Benign ★★ 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/hap1-p-pro37leu (accessed [today's date]).

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