Is HAP1 p.Ser616Ter (c.1847C>A) pathogenic?

HAP1 p.Ser616Ter (c.1847C>A) is classified Benign in HAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-11). Common (popmax 21.6%, afr) — too common for a highly-penetrant pathogenic allele.

HAP1 p.Ser616Ter

Q: How common is HAP1 p.Ser616Ter (c.1847C>A) in the general population?

HAP1 p.Ser616Ter (c.1847C>A) is common (popmax 21.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1847C>A · rs34381648 · VCV1287515

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Common

common (popmax 21.6%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (11 of 11) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -0.028, phastCons 0.007
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 21.6% African / African-American · 16,093/74,522 alleles

Filtering AF 21.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.2%

Overall 1.18% 18,757/1,592,356 alleles · common exomes 9,383/1,440,158 · genomes 9,374/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	21.6%	5
Remaining individualsnot grpmax-eligible	1.62%	62
Middle Eastern	1.57%	64
Admixed American	1.52%	66
South Asian	0.0644%	1,553
European (non-Finnish)	0.052%	1,925
East Asian	0.0383%	2,609
Ashkenazi Jewishnot grpmax-eligible	0.0103%	9,702
Finnishnot grpmax-eligible	0.00633%	15,791

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.Ser616Ter
Coding: c.1847C>A
MANE Select: NM_177977
dbSNP: rs34381648
Type: single nucleotide variant
Location: chr17:41724714 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28

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

Similar variants

HAP1 p.Arg106Pro Uncertain significance ★★ ⚠ same type
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.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-ser616ter (accessed [today's date]).

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