Is DHH p.Pro83Ser (c.247C>T) pathogenic?

DHH p.Pro83Ser (c.247C>T) is classified Uncertain significance in DHH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-06). AlphaMissense: likely benign (0.2468); Ultra-rare (popmax 0.012%, afr).

How common is DHH p.Pro83Ser (c.247C>T) in the general population?

DHH p.Pro83Ser (c.247C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about DHH p.Pro83Ser (c.247C>T)?

AlphaMissense predicts likely benign (score 0.2468) — an in-silico prediction, not a clinical call.

DHH p.Pro83Ser

c.247C>T · rs375841437 · VCV2683198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2468 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2468	likely benign
REVEL	0.689	pathogenic-leaning
SaProt	LLR -9.88	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 4,650 bp · p 8.5e-08 · regional, not allelic
Overall
CADD	25.3	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 0.012% African / African-American · 9/74,930 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000868% 14/1,613,458 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,326
Admixed American	0.00167%	60,004
European (non-Finnish)	0.000339%	295,000

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: DHH
Protein: p.Pro83Ser
Coding: c.247C>T
MANE Select: NM_021044
dbSNP: rs375841437
Type: single nucleotide variant
Location: chr12:49094266 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.87 · 5 PDB

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

Similar variants

DHH c.*401G>T Uncertain significance ★★ same type
DHH p.Ala287Glu Uncertain significance ★★ ⚠ same type
DHH p.Arg102His Uncertain significance ★★ ⚠ same type
DHH p.Arg309Leu Uncertain significance ★★ ⚠ same type
DHH p.Arg318Pro Uncertain significance ★★ ⚠ same type
DHH p.Ser210Arg Uncertain significance ★★ ⚠ same type
DHH c.303+66C>T Benign ★★ same type
DHH c.304-15T>C Likely 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/dhh-p-pro83ser (accessed [today's date]).

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