Is HAGH p.Pro176Ser (c.526C>T) pathogenic?

HAGH p.Pro176Ser (c.526C>T) is classified Uncertain significance in HAGH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-09). AlphaMissense: likely benign (0.1052); Very rare (popmax 0.00401%, afr).

How common is HAGH p.Pro176Ser (c.526C>T) in the general population?

HAGH p.Pro176Ser (c.526C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about HAGH p.Pro176Ser (c.526C>T)?

AlphaMissense predicts likely benign (score 0.1052) — an in-silico prediction, not a clinical call.

HAGH p.Pro176Ser

c.526C>T · VCV3856708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1052	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -9.49	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 3.6	GERP -1.1, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 18 kb · p 0.0043 · regional, not allelic
Overall
CADD	14.1	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 0.00401% African / African-American · 3/74,846 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000311% 5/1,609,370 alleles · very rare exomes 4/1,457,150 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,949
European (non-Finnish)	0.00017%	588,149

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: HAGH
Protein: p.Pro176Ser
Coding: c.526C>T
MANE Select: NM_005326
Type: single nucleotide variant
Location: chr16:1819130 (GRCh38)
Gene constraint: LOEUF 1.403 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.57 · 2 PDB

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

Similar variants

HAGH p.Ala15Val Uncertain significance ★ ⚠ same type
HAGH p.Ala187Val Uncertain significance ★ ⚠ same type
HAGH p.Ala18Val Uncertain significance ★ ⚠ same type
HAGH p.Ala264Thr Uncertain significance ★ ⚠ same type
HAGH p.Ala284Thr Uncertain significance ★ ⚠ same type
HAGH p.Arg232His Uncertain significance ★ ⚠ same type
HAGH p.Arg242Trp Uncertain significance ★ ⚠ same type
HAGH p.Arg294Gln Uncertain significance ★ ⚠ 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/hagh-p-pro176ser (accessed [today's date]).

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