Is HTRA2 p.Pro68Ser (c.202C>T) pathogenic?

HTRA2 p.Pro68Ser (c.202C>T) is classified Likely benign in HTRA2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0741); Rare (popmax 0.358%, afr).

How common is HTRA2 p.Pro68Ser (c.202C>T) in the general population?

HTRA2 p.Pro68Ser (c.202C>T) is rare (popmax 0.358%, afr) (gnomAD).

What do computational predictors say about HTRA2 p.Pro68Ser (c.202C>T)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

HTRA2 p.Pro68Ser

c.202C>T · rs146380692 · VCV726830

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.358%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -7.53	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 -0.016	GERP -3.4
Regional constraint	o/e 1.08	unconstrained · MANE · 442 bp · p 0.24 · regional, not allelic
Overall
CADD	3.387	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 0.358% African / African-American · 268/74,962 alleles

Filtering AF 0.322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.309%

Overall 0.0187% 302/1,611,082 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.358%	280
Remaining individualsnot grpmax-eligible	0.0289%	3,460
Admixed American	0.0184%	5,430
Middle Eastern	0.0165%	6,052
South Asian	0.0022%	45,400
European (non-Finnish)	0.00017%	589,449

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: HTRA2
Protein: p.Pro68Ser
Coding: c.202C>T
MANE Select: NM_013247
dbSNP: rs146380692
Type: single nucleotide variant
Location: chr2:74530208 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.83 · 13 PDB

Full HTRA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTRA2 p.Arg380Ter Pathogenic ★★ same type
HTRA2 p.Gln82Ter Pathogenic ★★ same type
AUP1 p.Pro9Ser Uncertain significance ★★ ⚠ same type
HTRA2 c.507-10T>A Uncertain significance ★★ same type
HTRA2 c.507-9C>A Uncertain significance ★★ same type
HTRA2 p.Ala110Gly Uncertain significance ★★ ⚠ same type
HTRA2 p.Ala415Thr Uncertain significance ★★ ⚠ same type
HTRA2 p.Arg252Gln 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/htra2-p-pro68ser (accessed [today's date]).

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