Is HR p.Ala656Pro (c.1966G>C) pathogenic?

HR p.Ala656Pro (c.1966G>C) is classified Uncertain significance in HR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.134); Ultra-rare (popmax 0.017%, eas); Associated with Inborn genetic diseases.

What condition is associated with HR p.Ala656Pro (c.1966G>C)?

HR p.Ala656Pro (c.1966G>C) is associated with Inborn genetic diseases (ClinVar).

How common is HR p.Ala656Pro (c.1966G>C) in the general population?

HR p.Ala656Pro (c.1966G>C) is ultra-rare (popmax 0.017%, eas) (gnomAD).

What do computational predictors say about HR p.Ala656Pro (c.1966G>C)?

AlphaMissense predicts likely benign (score 0.134) — an in-silico prediction, not a clinical call.

HR p.Ala656Pro

c.1966G>C · rs760814859 · VCV2491120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.134 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.134	likely benign
REVEL	0.443	indeterminate
SaProt	LLR -5.20	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 1.8	GERP -0.64, phastCons 0.92
Regional constraint	o/e 1.00	unconstrained · MANE · 8,242 bp · p 0.98 · regional, not allelic
Overall
CADD	21.1	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 0.017% East Asian · 7/41,284 alleles

Filtering AF 0.00792% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0056%

Overall 0.000578% 9/1,556,224 alleles · ultra-rare exomes 8/1,404,008 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.017%	5,898
Remaining individualsnot grpmax-eligible	0.00332%	30,132

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: HR
Protein: p.Ala656Pro
Coding: c.1966G>C
MANE Select: NM_005144
dbSNP: rs760814859
Type: single nucleotide variant
Location: chr8:22122829 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65

Full HR 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

HR p.Ala1188Asp Uncertain significance ★★ ⚠ same condition
HR p.Ala511Thr Uncertain significance ★★ ⚠ same condition
HR p.Ala555Thr Uncertain significance ★★ same condition
HR p.Ala900Thr Uncertain significance ★★ ⚠ same condition
HR p.Arg1095Trp Uncertain significance ★★ ⚠ same condition
HR p.Arg1096Gln Uncertain significance ★★ ⚠ same condition
HR p.Arg1097His Uncertain significance ★★ ⚠ same condition
HR p.Arg565Gln 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/hr-p-ala656pro (accessed [today's date]).

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