Is HAP1 p.Arg106Pro (c.317G>C) pathogenic?

HAP1 p.Arg106Pro (c.317G>C) is classified Uncertain significance in HAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-27). AlphaMissense: ambiguous (0.3557); Ultra-rare (popmax 0.0165%, mid).

How common is HAP1 p.Arg106Pro (c.317G>C) in the general population?

HAP1 p.Arg106Pro (c.317G>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about HAP1 p.Arg106Pro (c.317G>C)?

AlphaMissense predicts ambiguous (score 0.3557) — an in-silico prediction, not a clinical call.

HAP1 p.Arg106Pro

c.317G>C · VCV3856745

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3557 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3557	ambiguous
REVEL	0.195	benign-leaning
SaProt	LLR -5.63	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	23.0	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 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000435% 7/1,608,718 alleles · ultra-rare exomes 6/1,456,376 · genomes 1/152,342 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
African / African-American	0.008%	12,496

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.Arg106Pro
Coding: c.317G>C
MANE Select: NM_177977
Type: single nucleotide variant
Location: chr17:41734318 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 106: the hap1 n-terminal domain

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

Similar variants

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
HAP1 p.Thr66Ala Likely benign ★★ same type
HAP1 p.Val369Ala 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-arg106pro (accessed [today's date]).

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